2-(amino-substituted)-4-aryl pyrimidines and related compounds useful for treating inflammatory diseases

ABSTRACT

A heterocyclic inhibitor having the formula I, with the variables defined herein, which is useful for treating inflammatory and other physiological disorders in which PKC-theta isoform plays a role:

PRIORITY INFORMATION

The present application is a Continuation of U.S. application Ser. No.11/032,299, filed Jan. 10, 2005 now U.S. Pat. No. 7,732,444, whichclaims priority to U.S. Provisional Application No. 60/534,898, filedJan. 8, 2004, the entire contents of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

The protein kinase C family is a group of serine/threonine kinases thatis comprised of twelve related isoenzymes. These kinases are expressedin a wide range of tissues and cell types. The PKC-theta isoform ofprotein kinase C is selectively expressed in T lymphocytes and plays animportant role in the T cell antigen receptor (TCR)-triggered activationof mature T cells, and the subsequent release of cytokines such as IL-2and T cell proliferation (Isakov and Altman, Annu. Rev. Immunol., 2002,20, 761-94).

It has been well established that T cells play an important role inregulating the immune response (Powrie and Coffman, Immunology Today,1993, 14, 270). The activation of T cells is often the initiating eventin a variety of immunological disorders. It is believed that followingactivation of the TCR, there is an influx of calcium that is requiredfor T cell activation. Upon activation, T cells produce cytokines,including IL-2, leading to cell proliferation, differentiation, andeffector function. Clinical studies with inhibitors of IL-2 have shownthat interference with T cell activation and proliferation effectivelysuppresses immune response in vivo (Waldmann, Immunology Today, 1993,14, 264). Accordingly, agents that inhibit T lymphocyte activation andsubsequent cytokine production are therapeutically useful forselectively suppressing the immune response in a patient in need of suchimmunosuppression and therefore are useful in treating immunologicaldisorders such as autoimmune and inflammatory diseases.

Additionally, PKC-theta activation has been shown to play a role ininsulin resistance in skeletal muscle and therefore inhibitors ofPKC-theta may also be useful for treating type II diabetes (M. E.Griffen et al., Diabetes, 1999, 48, 1270). PKC-theta activation has alsobeen implicated in leukemia and thus inhibitors of PKC-theta may beuseful for the treatment of leukemia (Villalba and Altman, CurrentCancer Targets, 2002, 2, 125).

There remains a need to develop effective therapeutic agents for themajority of the diseases and disorders associated with activation ofPKC-theta. Accordingly, it would be beneficial to provide safe andeffective compounds that are useful as inhibitors of PKC-theta and thusin the treatment of disorders and diseases associated with activation ofPKC-theta.

SUMMARY OF THE INVENTION

This invention provides compounds that inhibit PKC-theta. Also providedare methods for the treatment of PKC-theta associated disorders,including inflammatory diseases, such as rheumatoid arthritis. Thecompounds of this invention are represented by formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,Q, Cy¹, and Cy² are described generally and in subsets herein.

In another embodiment of the present invention a pharmaceuticalcomposition is provided which comprises a pharmaceutically acceptablecarrier or diluent and a compound as disclosed herein. Thepharmaceutical compositions can be used in therapy, for example, totreat a subject with inflammatory and allergic disorders and diseasesincluding, but not limited to asthma, atopic dermatitis, allergicrhinitis, systemic anaphylaxis or hypersensitivity responses, drugallergies (e.g., to penicillin, cephalosporins), insect sting allergiesand dermatoses such as dermatitis, eczema, atopic dermatitis, allergiccontact dermatitis, urticaria, rheumatoid arthritis, osteoarthritis,inflammatory bowel disease e.g., such as ulcerative colitis, Crohn'sdisease, ileitis, Celiac disease, nontropical Sprue, enteritis,enteropathy associated with seronegative arthropathies, microscopic orcollagenous colitis, eosinophilic gastroenteritis, or pouchitisresulting after proctocolectomy, and ileoanal anastomosis, disorders ofthe skin [e.g., psoriasis, erythema, pruritis, and acne], multiplesclerosis, systemic lupus erythematosus, myasthenia gravis, juvenileonset diabetes, glomerulonephritis and other nephritides, autoimmunethyroiditis, Behcet's disease and graft rejection (including allograftrejection or graft-versus-host disease), stroke, cardiac ischemia,mastitis (mammary gland), vaginitis, cholecystitis, cholangitis orpericholangitis (bile duct and surrounding tissue of the liver), chronicbronchitis, chronic sinusitis, chronic inflammatory diseases of the lungwhich result in interstitial fibrosis, such as interstitial lungdiseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associatedwith rheumatoid arthritis, or other autoimmune conditions),hypersensitivity pneumonitis, collagen diseases, sarcoidosis, vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis),spondyloarthropathies, scleroderma, atherosclerosis, restenosis andmyositis (including polymyositis, dermatomyositis), pancreatitis andinsulin-dependent diabetes mellitus.

In another embodiment, the present invention provides a method ofinhibiting PKC theta activity in (a) a subject; or (b) a biologicalsample; which method comprises administering to said subject, orcontacting said biological sample with compounds as described herein, ora pharmaceutically acceptable salt or composition thereof.

Another embodiment of the present invention method is a method oftreating a subject with a PKC-theta mediated condition or disease, e.g.,a subject with asthma. The method comprises the step of administering tothe subject an effective amount of a PKC-theta inhibitor disclosedherein.

Yet another embodiment of the present invention is the use of one of thedisclosed PKC-theta inhibitors for the manufacture of a medicament fortreating a subject with a PKC-theta mediated condition or disease. Themedicament comprises an effective amount of the PKC-theta inhibitor.

DESCRIPTION OF THE INVENTION

I. General Description of Compounds of the Invention

The present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² are each independently H, C₁₋₃ alkyl or C₃₋₅cycloalkyl;

R³ is H or F;

R⁴ is H, F, —OR^(A), —C(O)R^(A), —C(O)OR^(A) or —N(R^(A))₂; or R³ and R⁴together with the carbon atom to which they are attached form a carbonylgroup; wherein each occurrence of R^(A) is independently H, C₁₋₃alkyl orC₃₋₅cycloalkyl;

Ring A is optionally substituted with 1 or 2 independent occurrences ofR⁵, wherein each R⁵ is independently selected from halo, C₁₋₄ aliphatic,—CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B),—C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C),—NR^(B)SO₂N(R^(B))₂, —NR^(B)SO₂R^(C), or C₁₋₄aliphatic optionallysubstituted with halo, —CN, —OR^(B), —SR^(C), —N(R^(B))₂,—NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B),—C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂,—S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, or —NR^(B)SO₂R^(C), wherein eachoccurrence of R^(B) is independently H or C₁₋₄aliphatic; or two R^(B) onthe same nitrogen atom taken together with the nitrogen atom form a 5-8membered aromatic or non-aromatic ring having in addition to thenitrogen atom 0-2 ring heteroatoms selected from N, O or S; and eachoccurrence of R^(C) is independently C₁₋₄ aliphatic;

Cy¹ is selected from:

-   -   a) a 6-membered aryl or heteroaryl ring substituted by one        occurrence of W at the meta or para position of the ring; or    -   b) a 5-membered heteroaryl ring substituted by one occurrence of        W;

wherein Cy¹ is optionally further substituted by one to threeindependent occurrences of R⁶, wherein each occurrence of R⁶ isindependently selected from -halo, C₁₋₈ aliphatic, —CN, —OR^(B),—SR^(D), —N(R^(E))₂, —NR^(E)C(O)R^(B), —NR^(E)C(O)N(R^(E))₂,—NR^(E)CO₂R^(D), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(E))₂, —OC(O)N(R^(E))₂,—S(O)₂R^(D), —SO₂N(R^(E))₂, —S(O)R^(D), —NR^(E)SO₂N(R^(E))₂,—NR^(E)SO₂R^(D), —C(═NH)—N(R^(E))₂, or C₁₋₈ aliphatic optionallysubstituted with halo, —CN, —OR^(B), —SR^(D), —N(R^(E))₂,—NR^(E)C(O)R^(B), —NR^(E)C(O)N(R^(E))₂, —NR^(E)CO₂R^(D), —CO₂R^(B),—C(O)R^(B), —C(O)N(R^(E))₂, —OC(O)N(R^(E))₂, —S(O)₂R^(D), —SO₂N(R^(E))₂,—S(O)R^(D), —NR^(E)SO₂N(R^(E))₂, —NR^(E)SO₂R^(D), or —C(═NH)—N(R^(E))₂,wherein each occurrence of R^(D) is C₁₋₆ aliphatic and each occurrenceof R^(E) is independently H, C₁₋₆ aliphatic, —C(═O)R^(B), —C(O)OR^(B) or—SO₂R^(B); or two R^(E) on the same nitrogen atom taken together withthe nitrogen atom form a 5-8 membered aromatic or non-aromatic ringhaving in addition to the nitrogen atom 0-2 ring heteroatoms selectedfrom N, O or S;

W is —R⁸, V—R⁸, L₁-R⁷, V-L₁-R⁷, L₁-V—R⁸, or L₁-V-L₂-R⁷; wherein:

-   -   L₁ and L₂ are each independently an optionally substituted C₁₋₆        alkylene chain;    -   V is —CH₂—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —CO₂—,        —NR^(E)—NR^(E)C(O)—, —NR^(E)CO₂—, —NR^(E)SO₂—, —C(O)N(R^(B))—,        —SO₂N(R^(B))—, —NR^(E)C(O)N(R^(B))— or —OC(O)—;    -   R⁷ is H, halo, —OH, —N(R^(F))₂, —CN, —OR^(G), —C(O)R^(G), —CO₂H,        —CO₂R^(G), —SR^(G), —S(O)R^(G), —S(O)₂R^(G), —N(R^(E))C(O)R^(G),        —N(R^(E))CO₂R^(G), —N(R^(E))SO₂R^(G), —C(O)N(R^(F))₂,        —SO₂N(R^(F))₂, —N(R^(E))C(O)N(R^(F))₂, —OC(O)R^(F) or an        optionally substituted group selected from C₁₋₁₀ aliphatic,        C₆₋₁₀aryl, 3-14 membered heterocyclyl or 5-14 membered        heteroaryl, wherein each occurrence of R^(F) is independently H,        C₁₋₆ aliphatic, C₆₋₁₀aryl, 3-14 membered heterocyclyl, 5-14        membered heteroaryl, —C(═O)R^(B), —C(O)OR^(B) or —SO₂R^(B); or        two R^(F) on the same nitrogen atom taken together with the        nitrogen atom form an optionally substituted 5-8 membered        aromatic or non-aromatic ring having in addition to the nitrogen        atom 0-2 ring heteroatoms selected from N, O or S; and each        occurrence of R^(G) is C₁₋₆ aliphatic, C₆₋₁₀aryl, 3-14 membered        heterocyclyl, or 5-14 membered heteroaryl;    -   R⁸ is an optionally substituted group selected from C₁₋₁₀        aliphatic, C₆₋₁₀ aryl, 3-14 membered heterocyclyl or 5-14        membered heteroaryl;

Q is a bond, CH₂ or C(═O);

Cy² is a C₆₋₁₀ aryl, a 5-10 membered heteroaryl, or a 5-10 memberedheterocyclyl ring, wherein each ring is optionally substituted by one tothree independent occurrences of R⁹ and one occurrence of R¹⁰,

wherein each occurrence of R⁹ is independently selected fromC₁₋₄aliphatic, —N(R^(B))₂, halo, NO₂, —CN, —OR^(B), —C(O)R^(A),—CO₂R^(A), —SR^(C), —S(O)R^(C), —S(O)₂R^(C), —OS(O)₂R^(C)—,N(R^(B))C(O)R^(A), —N(R^(B))CO₂R^(A), —N(R^(B))SO₂R^(A), —C(O)N(R^(B))₂,—SO₂N(R^(B))₂, —N(R^(B))C(O)N(R^(B))₂, —OC(O)R^(A), or C₁₋₄ aliphaticoptionally substituted by —N(R^(B))₂, halo, NO₂, —CN, —OR^(B),—C(O)R^(A), —CO₂R^(A), —SR^(C), —S(O)R^(C), —OS(O)₂R^(C), —S(O)₂R^(C),—N(R^(B))C(O)R^(A), —N(R^(B))CO₂R^(A), —N(R^(B))SO₂R^(A),—C(O)N(R^(B))₂, —SO₂N(R^(B))₂, —N(R^(B))C(O)N(R^(B))₂, or —OC(O)R^(A),and

R¹⁰ is selected from phenyl, or a 5-6 membered heterocyclyl orheteroaryl ring.

In certain embodiments, compounds of formula I are subject to one ormore, or all of, the following limitations:

-   1) when Cy¹ is phenyl substituted in the meta position with W then:

a) when W is —OMe, R¹, R², R³, and R⁴ are each hydrogen, and Q is abond, then when ring A is further substituted with R⁵, R⁵ is a groupother than —CF₃ or —C(O)N(R^(B))₂; and

b) when W is —OMe, R¹, R², R³, and R⁴ are each hydrogen, and Q is —CH₂—,then Cy² is other than 1H-benzimidazol-1-yl;

-   2) when Cy¹ is phenyl substituted in the para position with W, and    R¹, R², R³, and R⁴ are each hydrogen then:

a) when Q is a bond, W is other than:

-   -   i) —CONH₂;    -   ii) —CONHR⁸, where R⁸ is an optionally substituted group        selected from phenyl, -alkylphenyl, alkyl, or -alkylheterocycle;    -   iii) —CF₃;    -   iv) —SO₂Me;    -   v) —NH₂;    -   vi) -tBu;    -   vii) —CO₂H when Cy² is morpholine;    -   viii) —O(phenyl) when Cy² is indole; and    -   ix) —OMe;

b) when Q is —CH₂—, W is other than:

-   -   i) —CONH₂, when Cy² is optionally substituted imidazole or        benzimidazole;    -   ii) —CONHR⁸, where R⁸ is an optionally substituted group        selected from phenyl, -alkylphenyl, or -alkylheterocycle;    -   iii) —CF₃;    -   iv) —SO₂Me;    -   v) —OH, where Cy² is a 5-10 membered heterocyclyl ring;    -   vi) tBu, when Cy² is a 5-10 membered heterocyclyl ring; and    -   vii) —OMe; and

-   3) when Cy¹ is a 5-membered heteroaryl ring then:

a) when Cy¹ is isoxazole, R¹, R², R³, and R⁴ are each hydrogen, Q is abond, and W is p-fluoro-phenyl, then Cy² is a group other than pyridylor N-pyrrolidinyl;

b) when Cy¹ is triazolyl, R¹, R², R³, and R⁴ are each hydrogen, Q is abond, and W is —(CH₂)₂N(cyclopentyl)C(O)CH₂(naphthyl), then Cy² is agroup other than N-piperidinyl;

c) when Cy¹ is imidazolyl, R¹, R², R³, and R⁴ are each hydrogen, Q is abond, and W is meta-CF₃-phenyl, then R⁶ is a group other thanC(O)OCH₂CH₃; and

d) when Cy¹ is imidazol-5-yl and W is para-fluoro-phenyl, then R⁶ is agroup other than cyclohexyl.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic”, “cycloalkyl”, or“cycloalkenyl”). For example, suitable aliphatic groups includesubstituted or unsubstituted linear, branched or cyclic alkyl, alkenyl,alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Unless otherwise specified,in various embodiments, aliphatic groups have 1-20, 1-15, 1-12, 1-10,1-8, 1-6, 1-4, or 1-3 carbon atoms.

The terms “cycloaliphatic”, “carbocycle”, “carbocyclyl”, “carbocyclo”,or “carbocyclic”, used alone or as part of a larger moiety, refer to asaturated or partially unsaturated cyclic aliphatic ring system havingfrom 3 to about 14 members, wherein the aliphatic ring system isoptionally substituted. Cycloaliphatic groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,cyclooctenyl, and cyclooctadienyl. In some embodiments, the cycloalkylhas 3-6 carbons. The terms “cycloaliphatic”, “carbocycle”,“carbocyclyl”, “carbocyclo”, or “carbocyclic” also include aliphaticrings that are fused to one or more aromatic or nonaromatic rings, suchas decahydronaphthyl or tetrahydronaphthyl, where the radical or pointof attachment is on the aliphatic ring.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, substituted with one or more halogen atoms. As used herein, the term“halogen” or “halo” means F, Cl, Br, or I. Unless otherwise indicated,the terms “alkyl”, “alkenyl”, and “alkoxy” include haloalkyl,haloalkenyl and haloalkoxy groups, including, in particular, those with1-5 fluorine atoms. By way of example, the terms “C₁₋₃ aliphatic” and“C₁₋₃ alkyl” include within their scope trifluoromethyl andpentafluoroethyl groups.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to a C₆ to C₁₄aromatic moiety comprising one to three aromatic rings, which areoptionally substituted. Preferably, the aryl group is a C₆₋₁₀ arylgroup. Aryl groups include, without limitation, phenyl, naphthyl, andanthracenyl. The term “aryl”, as used herein, also includes groups inwhich an aromatic ring is fused to one or more heteroaryl,cycloaliphatic, or heterocyclyl rings, where the radical or point ofattachment is on the aromatic ring. Nonlimiting examples of such fusedring systems include indolyl, isoindolyl, benzothienyl, benzofuranyl,dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl, indanyl,phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl,benzodioxanyl, and benzodioxolyl. An aryl group may be mono-, bi-, tri-,or polycyclic, preferably mono-, bi-, or tricyclic, more preferablymono- or bicyclic. The term “aryl” may be used interchangeably with theterms “aryl group”, “aryl ring”, and “aromatic ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ aryl(C₁₋₆)alkyl,including, without limitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., heteroaralkyl, or “heteroaralkoxy”, refer to groupshaving 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to four heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heteroaryl” may be used interchangeably with the terms “heteroarylring”, “heteroaryl group”, or “heteroaromatic”, any of which termsinclude rings that are optionally substituted. The term “heteroaralkyl”refers to an alkyl group substituted by a heteroaryl, wherein the alkyland heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl) or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,and quinuclidinyl. The terms “heterocycle”, “heterocyclyl”,“heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and“heterocyclic radical”, are used interchangeably herein, and alsoinclude groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocyclyl ring. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aryl orheteroaryl moieties, as herein defined.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms is replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

An alkylene chain also can be optionally replaced by a functional group.An alkylene chain is “replaced” by a functional group when an internalmethylene unit is replaced with the functional group. Examples ofsuitable “replacing functional groups” are described in thespecification and claims herein.

The term “substituted”, as used herein, means that one or more hydrogensof the designated moiety are replaced, provided that the substitutionresults in a stable or chemically feasible compound. A stable compoundor chemically feasible compound is one in which the chemical structureis not substantially altered when kept at a temperature from about −80°C. to about +40°, in the absence of moisture or other chemicallyreactive conditions, for at least a week, or a compound which maintainsits integrity long enough to be useful for therapeutic or prophylacticadministration to a patient. The phrase “one or more substituents”, asused herein, refers to a number of substituents that equals from one tothe maximum number of substituents possible based on the number ofavailable bonding sites, provided that the above conditions of stabilityand chemical feasibility are met.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. In addition to the substituents defined above and herein,suitable substituents on the unsaturated carbon atom of an aryl orheteroaryl group also include and are generally selected from halogen;—R^(o); —OR^(o); —SR^(o); phenyl (Ph) optionally substituted with R^(o);—O(Ph) optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionallysubstituted with R^(o); —CH═CH(Ph), optionally substituted with R^(o);—NO₂; —CN; —N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o);—NR^(o)C(O)N(R^(o))₂; —NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o);—NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o)C(O)N(R^(o))₂;—NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o);—C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂; —OC(O)N(R^(o))₂;—OC(O)R^(o); —C(O)N(OR^(o))R^(o); —C(NOR^(o)) R^(o); —S(O)₂R^(o);—S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o); —NR^(o)SO₂N(R^(o))₂;—NR^(o)SO₂R^(o); —N(OR^(o))R^(o); —C(═NH)—N(R^(o))₂; —P(O)₂R^(o);—PO(R^(o))₂; —OPO(R^(o))₂; —(CH₂)₀₋₂NHC(O)R^(o); phenyl (Ph) optionallysubstituted with R^(o); —O(Ph) optionally substituted with R^(o);—(CH₂)₁₋₂(Ph), optionally substituted with R^(o); or —CH═CH(Ph),optionally substituted with R^(o); wherein each independent occurrenceof R^(o) is selected from hydrogen, optionally substituted C₁₋₆aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclicring, phenyl, —O(Ph), or —CH₂(Ph), or, notwithstanding the definitionabove, two independent occurrences of R^(o), on the same substituent ordifferent substituents, taken together with their intervening atom(s)form an optionally substituted 3-12 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In addition to the substituents defined above and herein, suitablesubstituents on the aliphatic group of R^(o) also include and aregenerally selected from NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂,halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H,CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic, whereineach of the foregoing C₁₋₄aliphatic groups of R^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise defined above and herein, suitablesubstituents on the saturated carbon of an aliphatic or heteroaliphaticgroup, or of a non-aromatic heterocyclic ring are selected from thoselisted above for the unsaturated carbon of an aryl or heteroaryl groupand additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group.

In addition to the substituents defined above and herein, optionalsubstituents on the nitrogen of a non-aromatic heterocyclic ring alsoinclude and are generally selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺,—C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺¹)₂,—C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionallysubstituted C₁₋₆ aliphatic, optionally substituted phenyl, optionallysubstituted —O(Ph), optionally substituted —CH₂(Ph), optionallysubstituted —(CH₂)₁₋₂(Ph); optionally substituted —CH═CH(Ph); or anunsubstituted 5-6 membered heteroaryl or heterocyclic ring having one tofour heteroatoms independently selected from oxygen, nitrogen, orsulfur, or, notwithstanding the definition above, two independentoccurrences of R⁺, on the same substituent or different substituents,taken together with their intervening atom(s) form an optionallysubstituted 3-12 membered saturated, partially unsaturated, or fullyunsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In addition to the substituents defined above and herein, optionalsubstituents on the aliphatic group or the phenyl ring of R⁺ alsoinclude and are generally selected from —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic),—NO₂, —CN, —CO₂H, —CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), orhalo(C₁₋₄ aliphatic), wherein each of the foregoing C₁₋₄aliphatic groupsof R⁺ is unsubstituted.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined in thespecification and claims herein), are taken together with theirintervening atom(s) to form an optionally substituted 3-12 memberedsaturated, partially unsaturated, or fully unsaturated monocyclic orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined in thespecification and claims herein), are taken together with theirintervening atom(s) include, but are not limited to the following: a)two independent occurrences of R^(o) (or R⁺, or any other variablesimilarly defined in the specification or claims herein) that are boundto the same atom and are taken together with that atom to form a ring,for example, N(R^(o))₂, where both occurrences of R^(o) are takentogether with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R^(o) (or R⁺, or any other variable similarly defined inthe specification or claims herein) that are bound to different atomsand are taken together with both of those atoms to form a ring, forexample where a phenyl group is substituted with two occurrences ofOR^(o)

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings (e.g., also spiro,and bridged rings) can be formed when two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined in thespecification and claims herein) are taken together with theirintervening atom(s) and that the examples detailed above are notintended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

3. Description of Exemplary Compounds

As described generally above for compounds of Formula I, R¹ and R² areeach independently H, C₁₋₃ alkyl or C₃₋₅ cycloalkyl, R³ is H or F, andR⁴ is H, F, —OR^(A), —C(O)R^(A), —C(O)OR^(A) or —N(R^(A))₂; or R³ and R⁴together with the carbon atom to which they are attached form a carbonylgroup; wherein each occurrence of R^(A) is independently H, C₁₋₃alkyl orC₃₋₅cycloalkyl. In certain exemplary embodiments, R¹ is H, —CH₃, orcyclopropyl. In other embodiments R¹ is H. In still other embodiments,R² is H or C₁-C₃alkyl. In other embodiments, R² is H, methyl, ethyl,propyl, or cyclopropyl. In yet other embodiments, R³ is H and R⁴ is H,methyl, or OH. In still other embodiments, both R³ and R⁴ are H. In yetother embodiments, R³ and R⁴ taken together with their interveningcarbon form a carbonyl group. In still other embodiments, R¹, R², R³,and R⁴ are all hydrogen.

As described generally above, Q is a bond, CH₂ or C(═O). In certainembodiments, Q is a bond.

As described generally above, Cy² is a C₆₋₁₀ aryl, a 5-10 memberedheteroaryl, or a 5-10 membered heterocyclyl ring, wherein each ring isoptionally substituted by one to three independent occurrences of R⁹ andone occurrence of R¹⁰. In some embodiments, Cy² is a C₆₋₁₀aryl or a5-10-membered heteroaryl ring. In other embodiments, Ring Cy² isselected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,tetrazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl,thienyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, oxazolyl,furanyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl,1,3-dihydroimidazol-2-onyl, benzo[1,3]dioxolyl, benzo[1,3]dioxinyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,[1,8]naphthyridinyl, naphthyl, 1,3-dihydro-benzoimidazol-2-on-1-yl,2-oxo-2,3-dihydrobenzooxazolyl, indolyl, benzo[c]isoxazolyl,benzofuranyl, benzothienyl, benzo[c]isothiazolyl, benzooxazol-2-yl,5H-pyrrolo[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, benzo[d]isothiazolyl, benzo[d]isoxazolyl,benzo[1,3]dioxolyl, benzothiazolyl, benzimidazolyl, indazolyl,3-1H-benzimidazol-2-one, tetrahydrofuranyl, morpholinyl,thiomorpholinyl, pyrrolidinyl, piperazinyl, or piperidinyl. In yet otherembodiments, Cy² is phenyl, pyridyl, naphthyl, thienyl,2-oxo-2,3-dihydrobenzooxazolyl, benzo[1,3]dioxolyl, benzo[1,3]dioxinyl,indolyl, tetrazole, piperidinyl, piperazinyl, or morpholinyl. In stillother embodiments, Cy² is phenyl or pyridyl. In yet other embodiments,Cy² is phenyl.

As described generally above, Cy² is optionally substituted by one tothree independent occurrences of R⁹ and one occurrence of R¹⁰, whereineach occurrence of R⁹ is independently selected from C₁₋₄aliphatic,—N(R^(B))₂, halo, NO₂, —CN, —OR^(B), —C(O)R^(A), —CO₂R^(A), —SR^(C),—S(O)R^(C), —S(O)₂R^(C), —OS(O)₂R^(C)—, N(R^(B))C(O)R^(A),—N(R^(B))CO₂R^(A), —N(R^(B))SO₂R^(A), —C(O)N(R^(B))₂, —SO₂N(R^(B))₂,—N(R^(B))C(O)N(R^(B))₂, —OC(O)R^(A), or C₁₋₄ aliphatic optionallysubstituted by —N(R^(B))₂, halo, NO₂, —CN, —OR^(B), —C(O)R^(A),—CO₂R^(A), —SR^(C), —S(O)R^(C), —OS(O)₂R^(C), —S(O)₂R^(C),—N(R^(B))C(O)R^(A), —N(R^(B))CO₂R^(A), —N(R^(B))SO₂R^(A),—C(O)N(R^(B))₂, —SO₂N(R^(B))₂, —N(R^(B))C(O)N(R^(B))₂, or —OC(O)R^(A),and R¹⁰ is selected from phenyl, or a 5-6 membered heterocyclyl orheteroaryl ring.

In certain exemplary embodiments, Cy² is unsubstituted, or issubstituted by one, two, or three occurrences of R⁹, wherein eachoccurrence of R⁹ is independently selected from —OR^(B),—N(R^(B))C(O)R^(A), —N(R^(B))₂, halo, C₁₋₄aliphatic optionallysubstituted by halo, NO₂, —OS(O)₂R^(C), —S(O)R^(C), —N(R^(B))SO₂R^(A),or —S(O)₂N(R^(B))₂. In still other embodiments, Cy² is unsubstituted, oris substituted by one, two, or three occurrences of R⁹, wherein eachoccurrence of R⁹ is independently selected from of —OR^(B),—N(R^(B))C(O)R^(A), —N(R^(B))₂, halo, —N(R^(B))SO₂R^(A),—S(O)₂N(R^(B))₂, or C₁₋₄aliphatic optionally substituted by halo. In yetother embodiments, Cy² is unsubstituted, or is substituted by one, two,or three occurrences of R⁹, wherein each occurrence of R⁹ isindependently selected from F, Cl, Br, —OR^(B), —NR^(B)C(O)R^(A),—N(R^(B))SO₂R^(A), —S(O)₂N(R^(B))₂, or C₁₋₄aliphatic optionallysubstituted by halo. In still other embodiments, Cy² is unsubstituted,or is substituted by one, two, or three occurrences of R⁹, wherein eachoccurrence of R⁹ is independently selected from F, Cl, Br, —OH,—NHC(O)CH₃, —NHSO₂CH₃, —OMe, methyl, ethyl, n-propyl, isopropyl,t-butyl, CF₃, or —S(O)₂NH₂. In yet other embodiments, Cy² isunsubstituted, or is substituted by one, two, or three occurrences ofR⁹, wherein each occurrence of R⁹ is independently selected from F, Cl,Br, —OH, —OMe, or methyl. In yet other embodiments, each occurrence ofR⁹ is independently halo or —OH.

Generally, ring A is optionally substituted with 1 or 2 independentoccurrences of R⁵, wherein each R⁵ is independently selected from halo,C₁₋₄ aliphatic, —CN, —OR^(B), —SR^(C), —N(R^(B))₂, —NR^(B)C(O)R^(B),—NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B), —C(O)R^(B),—C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, —S(O)₂R^(C), —SO₂N(R^(B))₂, —S(O)R^(C),—NR^(B)SO₂N(R^(B))₂, —NR^(B)SO₂R^(C), or C₁₋₄aliphatic optionallysubstituted with halo, —CN, —OR^(B), —SR^(C), —N(R^(B))₂,—NR^(B)C(O)R^(B), —NR^(B)C(O)N(R^(B))₂, —NR^(B)CO₂R^(C), —CO₂R^(B),—C(O)R^(B), —C(O)N(R^(B))₂, —OC(O)N(R^(B))₂, S(O)₂R^(C), —SO₂N(R^(B))₂,—S(O)R^(C), —NR^(B)SO₂N(R^(B))₂, or —NR^(B)SO₂R^(C), wherein eachoccurrence of R^(B) is independently H or C₁₋₄ aliphatic; or two R^(B)on the same nitrogen atom taken together with the nitrogen atom form a5-8 membered aromatic or non-aromatic ring having in addition to thenitrogen atom 0-2 ring heteroatoms selected from N, O or S; and eachoccurrence of R^(C) is independently C₁₋₄ aliphatic. In certainembodiments, R⁵ on ring A, when present, is selected from halo oroptionally substituted C₁₋₄ aliphatic. In other embodiments, R⁵ on ringA, when present, is selected from F, Cl, Br, or methyl. In certain otherembodiments, ring A is not substituted with R⁵.

As described generally above, Cy¹ is selected from a 6-membered aryl orheteroaryl ring substituted by one occurrence of W at the meta or paraposition of the ring, or a 5-membered heteroaryl ring substituted by oneoccurrence of W, wherein Cy¹ is optionally further substituted by one tothree independent occurrences of R⁶.

In certain embodiments, Cy¹ is selected from phenyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl,pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, thienyl, thiadiazolyl,thiadiazolyl, isoxazolyl, oxazolyl, furanyl, or oxadiazolyl. In certainother embodiments, Cy¹ is phenyl, pyridyl, pyrimidinyl, or thienyl. Inyet other embodiments, Cy¹ is phenyl, pyrid-3-yl, or thien-2-yl. Instill other embodiments, Cy¹ is phenyl.

As described above, Cy¹ is substituted by one occurrence of W, wherein Wis —R⁸, —V—R⁸, -L₁-R⁷, —V-L₁-R⁷, -L₁-V—R⁸, or -L₁-V-L₂-R⁷; wherein:

-   -   L₁ and L₂ are each independently an optionally substituted C₁₋₆        alkylene chain;    -   V is —CH₂—, —O—, —S—, —S(O)—, —S(O)₂—, —C(O)—, —CO₂—,        —NR^(E)—NR^(E)C(O)—, —NR^(E)CO₂—, —NR^(E)SO₂—, —C(O)N(R^(B))—,        —SO₂N(R^(B))—, —NR^(E)C(O)N(R^(B))— or —OC(O)—;    -   R⁷ is H, halo, —OH, —N(R^(F))₂, —CN, —OR^(G), —C(O)R^(G), —CO₂H,        —CO₂R^(G), —SR^(G), —S(O)R^(G), —S(O)₂R^(G), —N(R^(E))C(O)R^(G),        —N(R^(E))CO₂R^(G), —N(R^(E))SO₂R^(G), —C(O)N(R^(F))₂,        —SO₂N(R^(F))₂, —N(R^(E))C(O)N(R^(F))₂, —OC(O)R^(F) or an        optionally substituted group selected from C₁₋₁₀ aliphatic,        C₆₋₁₀aryl, 3-14 membered heterocyclyl or 5-14 membered        heteroaryl, wherein each occurrence of R^(F) is independently H,        C₁₋₆ aliphatic, C₆₋₁₀aryl, 3-14 membered heterocyclyl, 5-14        membered heteroaryl, —C(═O)R^(B), —C(O)OR^(B) of —SO₂R^(B); or        two R^(F) on the same nitrogen atom taken together with the        nitrogen atom form an optionally substituted 5-8 membered        aromatic or non-aromatic ring having in addition to the nitrogen        atom 0-2 ring heteroatoms selected from N, O or S; and each        occurrence of R^(G) is C₁₋₆ aliphatic, C₆₋₁₀aryl, 3-14 membered        heterocyclyl, or 5-14 membered heteroaryl; and    -   R⁸ is an optionally substituted group selected from C₁₋₁₀        aliphatic, C₆₋₁₀ aryl, 3-14-membered heterocyclyl or 5-14        membered heteroaryl.

In certain embodiments, each independent occurrence of L₁ and L₂ is anoptionally substituted C₁-C₄alkylene chain. In some embodiments, L₁ is—(CH₂)_(n), where n is 1-4, and wherein one hydrogen atom on anymethylene unit is optionally substituted, and L₂ is —(CH₂)_(m), where mis 1-4, and wherein one hydrogen atom on any methylene unit isoptionally substituted. In other embodiments, L₁ is —(CH₂)_(n), where nis 1-2, and wherein one hydrogen atom on any methylene unit isoptionally substituted with C₁₋₃alkyl, —OH, —O(C₁₋₃alkyl), —COOH, or—COO(C₁₋₃alkyl), and L₂ is —(CH₂)_(m), where m is 1-3, and wherein onehydrogen atom on any methylene unit is optionally substituted withC₁₋₃alkyl, —OH, —O(C₁₋₃alkyl), —COOH, or —COO(C₁₋₃alkyl). In otherembodiments, L₁ is —CH(CH₃)(CH₂)_(n), where n is 0-3. In still otherembodiments, L₁ is —CH(OH)(CH₂)_(n), where n is 0-3. In yet otherembodiments, L₂ is —(CH₂)_(m)CHCOOH—, where m is 1 or 2.

In certain embodiments, V is —O—, —NR^(E)—, —NR^(E)C(O)—, —NR^(E) CO₂—,—NR^(E)SO₂—, —C(O)N(R^(B))—, —CO₂—, or —SO₂N(R^(B))—, where R^(B) isindependently H or C₁₋₄ aliphatic and R^(E) is independently H, C₁₋₆aliphatic, —C(═O)R^(B), —C(O)OR^(B) or —SO₂R^(B); or two R^(E) on thesame nitrogen atom taken together with the nitrogen atom form a 5-8membered aromatic or non-aromatic ring having in addition to thenitrogen atom 0-2 ring heteroatoms selected from N, O or S. In yet otherembodiments, V is —O—, —NR^(E) —, C(O)N(R^(B))—, or —NR^(E)C(O)—. Instill other embodiments, V is —NR^(E)—.

In some embodiments, R⁷ is —N(R^(F))₂, —OR^(G), —N(R^(E))C(O)R^(G),—N(R^(E))CO₂R^(G), —N(R^(E))SO₂R^(G), —C(O)N(R^(F))₂, —SO₂N(R^(F))₂, anoptionally substituted 5- or 6-membered aryl or heteroaryl group, or anoptionally substituted 3-8-membered monocyclic or bicyclic heterocyclylgroup. In other embodiments, R⁷ is selected from —NH₂, —NH(C₁₋₅alkyl),—N(C₁₋₅alkyl)₂, —NHCO₂(C₁₋₆alkyl), —NHCO(C₁₋₆alkyl), —NHCO(optionallysubstituted phenyl), —NHSO₂(C₁₋₆alkyl), or an optionally substitutedgroup selected from C₁₋₆alkyl, phenyl, pyridyl, piperidinyl,piperazinyl, pyrrolidinyl, or azetidinyl, wherein the C₁₋₅alkyl group isoptionally substituted and is linear, cyclic, or branched.

In some embodiments, R⁸ is an optionally substituted group selected fromC₁₋₆alkyl, phenyl, pyridyl, piperidinyl, piperazinyl, pyrrolidinyl, orazetidinyl.

It will be appreciated that in some embodiments, R⁷ and R⁸ areoptionally substituted at one or more carbon atoms with 1, 2, or 3independent occurrences of R¹¹, and at one or more substitutablenitrogen atoms with R¹², wherein each occurrence of R¹¹ is independentlyselected from optionally substituted C₁₋₆aliphatic, optionallysubstituted 6-10-membered aryl, optionally substituted 5-10-memberedheteroaryl, —N(R^(B))₂, ═O, halo, NO₂, —CN, —OR^(B), —C(O)R^(A),—CO₂R^(A), —SR^(C), —S(O)R^(C), —S(O)₂R^(C), —OS(O)₂R^(C)—,N(R^(B))C(O)R^(A), —N(R^(B))CO₂R^(A), —N(R^(B))SO₂R^(A), —C(O)N(R^(B))₂,—SO₂N(R^(B))₂, —N(R^(B))C(O)N(R^(B))₂, or —OC(O)R^(A), and eachoccurrence of R¹² is independently selected from H, optionallysubstituted C₁₋₆ aliphatic, optionally substituted 6-10-membered aryl,optionally substituted 5-10-membered heteroaryl, —C(═O)R^(B),—C(O)OR^(B) or —SO₂R^(B).

In certain other embodiments, W is -L₁-V-L₂-R⁷, wherein L₁ is —CHR¹³—,where R¹³ is C₁₋₃alkyl, OH, or OMe, V is NR^(E), L₂ is —(CH₂)_(n)—,where n is 1-3, and R⁷ is —N(R^(F))₂, NR^(E)COOR^(G), NR^(E)COR^(G),NR^(E)SO₂R^(G), an optionally substituted 5-6-membered aryl orheteroaryl group, or an optionally substituted 3-8-membered heterocyclylgroup. In still other embodiments, R⁷ is —N(R^(F))₂, NR^(E)COOR^(G),NR^(E)COR^(G), NR^(E)SO₂R^(G), or an optionally substituted groupselected from phenyl, pyridyl, piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, or azetidinyl. In yet other embodiments, R⁷ is —N(R^(F))₂,NHCOOR^(G), NHCOR^(G), NHSO₂R^(G), or an optionally substituted groupselected from phenyl, pyridyl, piperidinyl, piperazinyl, orpyrrolidinyl. In certain other embodiments for compounds describeddirectly above, R^(F) is H or C₁₋₃alkyl. R^(G) is C₁₋₆alkyl or a5-6-membered aryl or heteroaryl group, and R^(E) is H, C₁₋₃alkyl, orSO₂CH₃.

In yet other embodiments W is selected from:

wherein m is 1, 2, or 3, R^(F) is H or C₁₋₃alkyl, and R^(E) is H,C₁₋₃alkyl, or SO₂CH₃, and wherein each of the foregoing pyridyl,pyrrolidinyl, piperidinyl, and piperazinyl groups is optionallysubstituted at one or more carbon atoms with 1, 2, or 3 independentoccurrences of R¹¹, and at one or more substitutable nitrogen atoms withR¹². In certain embodiments, each of the foregoing pyridyl,pyrrolidinyl, piperidinyl, and piperazinyl groups is unsubstituted.

In still other embodiments, W is —V—R⁸. In one embodiment, V is —NH— andR⁸ is optionally substituted piperidinyl, azetidinyl, or pyrrolidinyl.In other embodiments, V is —O— or —COO—, and R⁸ is C₁₋₆alkyl. In stillother embodiments, V is —CH₂— or SO₂, and R⁸ is an optionallysubstituted group selected from:

wherein each of the foregoing R⁸ groups is optionally substituted at oneor more carbon atoms with 1, 2, or 3 independent occurrences of R¹¹, andat one or more substitutable nitrogen atoms with R¹², wherein eachoccurrence of R¹¹ is independently selected from optionally substitutedC₁₋₆aliphatic, optionally substituted 6-10-membered aryl, optionallysubstituted 5-10-membered heteroaryl, —N(R^(B))₂, ═O, halo, NO₂, —CN,—OR^(B), —C(O)R^(A), —CO₂R^(A), —SR^(C), —S(O)R^(C), —S(O)₂R^(C),—OS(O)₂R^(C)—, N(R^(B))C(O)R^(A), —N(R^(B))CO₂R^(A), —N(R^(B))SO₂R^(A),—C(O)N(R^(B))₂, —SO₂N(R^(B))₂, —N(R^(B))C(O)N(R^(B))₂, and —OC(O)R^(A),and each occurrence of R¹² is independently selected from H, optionallysubstituted C₁₋₆ aliphatic, optionally substituted 6-10-membered aryl,optionally substituted 5-10-membered heteroaryl, —C(═O)R^(B),—C(O)OR^(B) or —SO₂R^(B). In certain embodiments, R⁸ is unsubstituted.In yet other embodiments, R⁸ is substituted on one or two carbon atomswith one or two occurrences of C₁₋₄alkyl, phenyl, heteroaryl, halo,—COOH, —COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂,—CONH(heteroaryl), —CN, —NH₂, —OH, —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, ═O, or C₁₋₄alkyl substituted with one or two independentoccurrences of phenyl, heteroaryl, halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂,—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN, —NH₂, —OH,—O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), or —N(C₁₋₄alkyl)₂. In still otherembodiments, R₈ is substituted on one nitrogen atom with —C₁₋₄alkyl, or—COO(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl). In certain embodiments for compoundsdescribed directly above, when V is —SO₂—, R⁸ is not ring g. In otherembodiments, for compounds described directly above, V is —CH₂—.

In yet other embodiments, V is —CH₂— and R⁸ is a group selected from:

In certain other embodiments W is -L₁-V—R⁸, wherein L₁ is —CH₂—, V is—NR^(E)— or —NR^(E)CO—, and R⁸ is an optionally substituted groupselected from C₁₋₆alkyl, or a 5-6-membered heteroaryl or a 3-7-memberedheterocyclyl group. In certain embodiments, R⁸ is an optionallysubstituted group selected from C₁₋₆alkyl, piperidinyl, pyrrolidinyl,azetidinyl, pyrazinyl, pyridyl, or pyrimidinyl. In still otherembodiments, R⁸ is an optionally substituted group selected from:

In yet other embodiments W is an optionally substituted group selectedfrom:

It will be appreciated that for compounds described directly above whereW is -L₁-V—R⁸, each of the R⁸ groups described directly is optionallysubstituted at one or more carbon atoms with 1, 2, or 3 independentoccurrences of R¹¹, and at one or more substitutable nitrogen atoms withR¹², wherein each occurrence of R¹¹ is independently selected fromoptionally substituted C₁₋₆aliphatic, optionally substituted6-10-membered aryl, optionally substituted 5-10-membered heteroaryl,—N(R^(B))₂, ═O, halo, NO₂, —CN, —OR^(B), —C(O)R^(A), —CO₂R^(A), —SR^(C),—S(O)R^(C), —S(O)₂R^(C), —OS(O)₂R^(C)—, N(R^(B))C(O)R^(A),—N(R^(B))CO₂R^(A), —N(R^(B))SO₂R^(A), —C(O)N(R^(B))₂, —SO₂N(R^(B))₂,N(R^(B))C(O)N(R^(B))₂, and —OC(O)R^(A), and each occurrence of R¹² isindependently selected from H, optionally substituted C₁₋₆ aliphatic,optionally substituted 6-10-membered aryl, optionally substituted5-10-membered heteroaryl, —C(═O)R^(B), —C(O)OR^(B) or —SO₂R^(B). Incertain embodiments, R⁸ is unsubstituted. In yet other embodiments, R⁸is substituted on one or two carbon atoms with one or two occurrences ofC₁₋₄alkyl, phenyl, heteroaryl, halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂,—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN, —NH₂, —OH,—O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, ═O, or C₁₋₄alkylsubstituted with one or two independent occurrences of phenyl,heteroaryl, halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl),—CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN, —NH₂, —OH, —NH(C₁₋₄alkyl), or—N(C₁₋₄alkyl)₂. In still other embodiments, R₈ is substituted on onenitrogen atom with —C₁₋₄alkyl, or —COO(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl),benzyl, or CH₂(heteroaryl). In still other embodiments, R⁸ issubstituted with one or two occurrences of —CF₃, halo, C₁₋₃alkyl, orCOO(C₁₋₃alkyl), and is substituted on one nitrogen atom with —C₁₋₄alkyl,or —COO(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), benzyl, or CH₂(heteroaryl).

As also described above, Cy¹ is optionally further substituted by one tothree independent occurrences of R⁶, wherein each occurrence of R⁶ isindependently selected from -halo, C₁₋₈ aliphatic, —CN, —OR^(B),—SR^(D), —N(R^(E))₂, —NR^(E)C(O)R^(B), —NR^(E)C(O)N(R^(E))₂,—NR^(E)CO₂R^(D), —CO₂R^(B), —C(O)R^(B), —C(O)N(R^(E))₂, —OC(O)N(R^(E))₂,—S(O)₂R^(D), —SO₂N(R^(E))₂, —S(O)R^(D), —NR^(E)SO₂N(R^(E))₂,—NR^(E)SO₂R^(D), —C(═NH)—N(R^(E))₂, or C₁₋₈ aliphatic optionallysubstituted with halo, —CN, —OR^(B), —SR^(D), —N(R^(E))₂,—NR^(E)C(O)R^(B), —NR^(E)C(O)N(R^(E))₂, —NR^(E)CO₂R^(D), —CO₂R^(B),—C(O)R^(B), —C(O)N(R^(E))₂, —OC(O)N(R^(E))₂, —S(O)₂R^(D), —SO₂N(R^(E))₂,—S(O)R^(D), —NR^(E)SO₂N(R^(E))₂, —NR^(E)SO₂R^(D), or —C(═NH)—N(R^(E))₂,wherein each occurrence of R^(D) is C₁₋₆ aliphatic and each occurrenceof R^(E) is independently H, C₁₋₆ aliphatic, —C(═O)R^(B), —C(O)OR^(B) or—SO₂R^(B); or two R^(E) on the same nitrogen atom taken together withthe nitrogen atom form a 5-8 membered aromatic or non-aromatic ringhaving in addition to the nitrogen atom 0-2 ring heteroatoms selectedfrom N, O or S. In certain embodiments, Cy¹ is optionally furthersubstituted with one occurrence of R⁶, wherein R⁶ is selected from—OR^(B), C₁₋₃aliphatic, or halo. In yet other embodiments, R⁶ isselected from —OMe, methyl, ethyl, F, or Cl.

In certain other exemplary embodiments, for compounds of general formulaI, Cy¹ is optionally substituted phenyl and thus compounds of formulaI-A are provided:

wherein W, R¹, R², R³, R⁴, Q and Cy² are defined generally and insubsets above.

In still other embodiments, for compounds of formula I-A, R¹, R², R³,and R⁴ are all hydrogen, and Q is a bond and compounds of formula I-A-iare provided:

wherein W and Cy² are defined generally and in subsets above.

In certain embodiments, for compounds described directly above, compoundvariables are selected from one or more, or all of:

a. Cy² is a C₆₋₁₀aryl or a 5-10-membered heteroaryl ring optionallysubstituted by one to three independent occurrences of R⁹ and oneoccurrence of R¹⁰, wherein each occurrence of R⁹ is independentlyselected from —OR^(B), —N(R^(B))C(O)R^(A), —N(R^(B))₂, halo,C₁₋₄aliphatic optionally substituted by halo, NO₂, —OS(O)₂R^(C),—S(O)R^(C), —N(R^(B))SO₂R^(A), or —S(O)₂N(R^(B))₂;

b. ring A is optionally substituted with 1 or 2 independent occurrencesof R⁵, wherein R⁵ on ring A, when present, is selected from halo oroptionally substituted C₁₋₄ aliphatic;

c. W is selected from one of:

-   -   i) -L₁-V-L₂-R⁷, wherein L₁ is —CHR¹³—, where R¹³ is C₁₋₃alkyl,        OH, or OMe, V is NR^(E), L₂ is —(CH₂)_(n)—, where n is 1-3, and        R⁷ is —N(R^(F))₂, NR^(E)COOR^(G), NR^(E)COR^(G), NR^(E)SO₂R^(G),        an optionally substituted 5-6-membered aryl or heteroaryl group,        or an optionally substituted 3-8-membered heterocyclyl group;    -   ii) —V—R⁸, wherein V is —NH— and R⁸ is optionally substituted        group selected from piperidinyl, azetidinyl, or pyrrolidinyl; V        is —O— or —COO—, and R⁸ is C₁₋₆alkyl; or V is —CH₂— or SO₂, and        R⁸ is an optionally substituted group selected from:

-   -   wherein R⁸ is substituted on one or two carbon atoms with one or        two occurrences of C₁₋₄alkyl, phenyl, heteroaryl, halo, —COOH,        —COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂,        —CONH(heteroaryl), —CN, —NH₂, —OH, —O(C₁₋₄alkyl),        —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, ═O, or C₁₋₄alkyl substituted        with one or two independent occurrences of phenyl, heteroaryl,        halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl),        —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN, —NH₂, —OH,        —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), or —N(C₁₋₄alkyl)₂; or    -   iii)-L₁-V—R⁸, wherein L₁ is —CH₂—, V is —NR^(E)— or —NR^(E)CO—,        and R⁸ is an optionally substituted group selected from        C₁₋₆alkyl, or a 5-6-membered heteroaryl or a 3-7-membered        heterocyclyl group, wherein R⁸ is unsubstituted, or R⁸ is        substituted on one or two carbon atoms with one or two        occurrences of C₁₋₄alkyl, phenyl, heteroaryl, halo, —COON,        —COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂,        —CONH(heteroaryl), —CN, —NH₂, —OH, —O(C₁₋₄alkyl),        —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, ═O, or C₁₋₄alkyl substituted        with one or two independent occurrences of phenyl, heteroaryl,        halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl),        —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN, —NH₂, —OH,        —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), or —N(C₁₋₄alkyl)₂, and R₈ is        optionally substituted on one nitrogen atom with —C₁₋₄alkyl, or        —COO(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), benzyl, or CH₂(heteroaryl);        and

d) Cy¹ is optionally further substituted by one to three independentoccurrences of R⁶, wherein each occurrence of R⁶ is independentlyselected from —OR^(B), C₁₋₃aliphatic, or halo.

In certain other embodiments, for compounds described directly above,compound variables are selected from one or more, or all of:

a. Cy² is phenyl, pyridyl, naphthyl, thienyl,2-oxo-2,3-dihydrobenzooxazolyl, benzo[1,3]dioxolyl, benzo[1,3]dioxinyl,indolyl, tetrazole, piperidinyl, piperazinyl, or morpholinyl optionallysubstituted by one to three independent occurrences of R⁹ and oneoccurrence of R¹⁰, wherein each occurrence of R⁹ is independentlyselected from —OR^(B), —N(R^(B))C(O)R^(A), —N(R^(B))₂, halo,C₁₋₄aliphatic optionally substituted by halo, NO₂, —OS(O)₂R^(C),—S(O)R^(B), —N(R^(B))SO₂R^(A), or —S(O)₂N(R^(B))₂;

b. ring A is optionally substituted with 1 or 2 independent occurrencesof R⁵, wherein R⁵ on ring A, when present, is selected from F, Cl, Br,or methyl;

c. W is selected from:

-   -   i)

-   -   wherein m is 1, 2, or 3, R^(F) is H or C₁₋₃alkyl, and R^(E) is        H, C₁₋₃alkyl, or SO₂CH₃, and wherein each of the foregoing        pyridyl, pyrrolidinyl, piperidinyl, and piperazinyl groups is        optionally substituted at one or more carbon atoms with 1, 2, or        3 independent occurrences of R¹¹, and at one or more        substitutable nitrogen atoms with R¹²;    -   ii) —V—R⁸, wherein V is —CH₂— and R⁸ is a group selected from:

-   -   iii)

-   -   wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are        unsubstituted, or are substituted on one or two carbon atoms        with one or two occurrences of C₁₋₄alkyl, phenyl, heteroaryl,        halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl),        —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN, —NH₂, —OH,        —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, ═O, or C₁₋₄alkyl        substituted with one or two independent occurrences of phenyl,        heteroaryl, halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂,        —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN,        —NH₂, —OH, —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), or —N(C₁₋₄alkyl)₂, and        are optionally substituted on one nitrogen atom with —C₁₋₄alkyl,        or —COO(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), benzyl, or CH₂(heteroaryl);        and

d) Cy¹ is optionally further substituted by one to three independentoccurrences of R⁶, wherein each occurrence of R⁶ is —OMe, methyl, ethyl,F, or Cl.

In yet other exemplary embodiments, for compounds of general formula I,Cy¹ is optionally substituted thienyl and thus compounds of formula I-Bare provided:

wherein W, R¹, R², R³, R⁴, Q and Cy² are defined generally and insubsets above.

In still other embodiments, for compounds of formula I-B, R¹, R², R³,and R⁴ are all hydrogen, and Q is a bond and compounds of formula I-B-iare provided:

wherein W and Cy² are defined generally and in subsets above.

In certain embodiments, for compounds described directly above, compoundvariables are selected from one or more, or all of:

a. Cy² is a C₆₋₁₀aryl or a 5-10-membered heteroaryl ring optionallysubstituted by one to three independent occurrences of R⁹ and oneoccurrence of R¹⁰, wherein each occurrence of R⁹ is independentlyselected from —OR^(B), —N(R^(B))C(O)R^(A), —N(R^(B))₂, halo,C₁₋₄aliphatic optionally substituted by halo, NO₂, —OS(O)₂R^(C),—S(O)R^(C), —N(R^(B))SO₂R^(A), or —S(O)₂N(R^(B))₂;

b. ring A is optionally substituted with 1 or 2 independent occurrencesof R⁵, wherein R⁵ on ring A, when present, is selected from halo oroptionally substituted C₁₋₄ aliphatic;

c. W is -L₁-V—R⁸, wherein L₁ is —CH₂—, V is —NR^(E)— or —NR^(E)CO—, andR⁸ is an optionally substituted group selected from C₁₋₆alkyl, or a5-6-membered heteroaryl or a 3-7-membered heterocyclyl group, wherein R⁸is unsubstituted, or R⁸ is substituted on one or two carbon atoms withone or two occurrences of C₁₋₄alkyl, phenyl, heteroaryl, halo, —COOH,—COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄allyl)₂,—CONH(heteroaryl), —CN, —NH₂, —OH, —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, ═O, or C₁₋₄allyl substituted with one or two independentoccurrences of phenyl, heteroaryl, halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂,—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN, —NH₂, —OH,—O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), or —N(C₁₋₄alkyl)₂, and R₈ is optionallysubstituted on one nitrogen atom with —C₁₋₄alkyl, or —COO(C₁₋₄alkyl),—SO₂(C₁₋₄alkyl), benzyl, or CH₂(heteroaryl); and

d) Cy¹ is optionally further substituted by one to three independentoccurrences of R⁶, wherein each occurrence of R⁶ is independentlyselected from —OR^(B), C₁₋₃aliphatic, or halo.

In certain other embodiments, for compounds described directly above,compound variables are selected from one or more, or all of:

a. Cy² is phenyl, pyridyl, naphthyl, thienyl,2-oxo-2,3-dihydrobenzooxazolyl, benzo[1,3]dioxolyl, benzo[1,3]dioxinyl,indolyl, tetrazole, piperidinyl, piperazinyl, or morpholinyl optionallysubstituted by one to three independent occurrences of R⁹ and oneoccurrence of R¹⁰, wherein each occurrence of R⁹ is independentlyselected from —OR^(B), —N(R^(B))C(O)R^(A), —N(R^(B))₂, halo,C₁₋₄aliphatic optionally substituted by halo, NO₂, —OS(O)₂R^(C),—S(O)R^(C), —N(R^(B))SO₂R^(A), or —S(O)₂N(R^(B))₂;

b. ring A is optionally substituted with 1 or 2 independent occurrencesof R⁵, wherein R⁵ on ring A, when present, is selected from F, Cl, Br,or methyl;

c. W is:

wherein the pyrrolidinyl, piperidinyl, and pyridyl groups areunsubstituted, or are substituted on one or two carbon atoms with one ortwo occurrences of C₁₋₄alkyl, phenyl, heteroaryl, halo, —COOH,—COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂,—CONH(heteroaryl), —CN, —NH₂, —OH, —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, ═O, or C₁₋₄alkyl substituted with one or two independentoccurrences of phenyl, heteroaryl, halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂,—CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN, —NH₂, —OH,—O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), or —N(C₁₋₄alkyl)₂, and are optionallysubstituted on one nitrogen atom with —C₁₋₄alkyl, or —COO(C₁₋₄alkyl),—SO₂(C₁₋₄alkyl), benzyl, or CH₂(heteroaryl); and

d) Cy¹ is optionally further substituted by one to three independentoccurrences of R⁶, wherein each occurrence of R⁶ is —OMe, methyl, ethyl,F, or Cl.

In still other embodiments, compounds of formula I-A-i are provided:

wherein

a. Cy² is phenyl optionally substituted by one to three independentoccurrences of R⁹ and one occurrence of R¹⁰, wherein each occurrence ofR⁹ is independently selected from —OR^(B), —N(R^(B))C(O)R^(A),—N(R^(B))₂, halo, C₁₋₄aliphatic optionally substituted by halo, NO₂,—OS(O)₂R^(C), —S(O)R^(C), —N(R^(B))SO₂R^(A), or —S(O)₂N(R^(B))₂;

b. ring A is optionally substituted with 1 or 2 independent occurrencesof R⁵, wherein R⁵ on ring A, when present, is selected from F, Cl, Br,or methyl;

c. W is selected from:

-   -   i)

-   -   wherein m is 1, 2, or 3, R^(F) is H or C₁₋₃alkyl, and R^(E) is        H, C₁₋₃alkyl, or SO₂CH₃, and wherein each of the foregoing        pyridyl, pyrrolidinyl, piperidinyl, and piperazinyl groups is        optionally substituted at one or more carbon atoms with 1, 2, or        3 independent occurrences of R¹¹, and at one or more        substitutable nitrogen atoms with R¹²;    -   ii) —V—R⁸, wherein V is —CH₂— and R⁸ is a group selected from:

-   -   iii)

-   -   wherein the pyrrolidinyl, piperidinyl, and pyridyl groups are        unsubstituted, or are substituted on one or two carbon atoms        with one or two occurrences of C₁₋₄alkyl, phenyl, heteroaryl,        halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂, —CONH(C₁₋₄alkyl),        —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN, —NH₂, —OH,        —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, ═O, or C₁₋₄alkyl        substituted with one or two independent occurrences of phenyl,        heteroaryl, halo, —COOH, —COO(C₁₋₄alkyl), —CONH₂,        —CONH(C₁₋₄alkyl), —CON(C₁₋₄alkyl)₂, —CONH(heteroaryl), —CN,        —NH₂, —OH, —O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), or —N(C₁₋₄alkyl)₂, and        are optionally substituted on one nitrogen atom with —C₁₋₄alkyl,        or —COO(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), benzyl, or CH₂(heteroaryl);        and

d) Cy¹ is optionally further substituted by one to three independentoccurrences of R⁶, wherein each occurrence of R⁶ is —OMe, methyl, ethyl,F, or Cl.

In certain other embodiments, for compounds described directly above,Cy² is optionally further substituted with one or two occurrences of R⁹,wherein R⁹ is halo. In yet other embodiments, ring A is not furthersubstituted by R⁵. In still other embodiments, Cy¹ is optionally furthersubstituted by one occurrence of F or methyl.

The following chemical structures are examples of specific compounds ofthe invention:

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areuseful as inhibitors of PKC-theta, and thus the present compounds areuseful for treating or lessening the severity of a variety of acute orchronic inflammatory or autoimmune diseases, conditions, or disorders,including, but not limited to, rheumatoid arthritis (RA),osteoarthritis, multiple sclerosis (MS), inflammatory bowel disease(IBD), psoriasis, organ transplantation, graft vs. host disease, asthmaand chronic obstructive pulmonary disease (COPD).

Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of PKC-theta.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of an acute or chronic inflammatory or autoimmune disease ordisorder is provided comprising administering an effective amount of acompound, or a pharmaceutically acceptable composition comprising acompound to a subject in need thereof.

In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of an acute or chronicinflammatory or autoimmune disease or disorder. In other embodiments, an“effective amount” of a compound or composition of the inventionincludes those amounts that antagonize or inhibit PKC-theta. An amountwhich antagonizes or inhibits PKC-theta is detectable, for example, byany assay capable of determining PKC-theta activity, including the onedescribed below as an illustrative testing method.

In other embodiments, an “effective amount” of a compound can achieve adesired therapeutic and/or prophylactic effect, such as an amount whichresults in the prevention of or a decrease in the symptoms associatedwith a disease mediated by the inappropriate activation of PKC-theta andsubsequently the inappropriate activation of T cells.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of anacute or chronic inflammatory disease or disorder. The exact amountrequired will vary from subject to subject, depending on the species,age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The compounds of the invention are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an, oil vehicle. Injectable depot formsare made by forming microencapsule matrices of the compound inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of compound to polymer and the nature of the particularpolymer employed, the rate of compound release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, t) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of PKC-theta and thus the invention further relates to amethod for treating (e.g., palliative, curative, prophylactic) a diseaseor disorder associated with PKC-theta activation including but notlimited to inflammatory diseases, autoimmune diseases, organ and bonemarrow transplant rejection and other disorders associated with T cellmediated immune response, including acute or chronic inflammation,allergies, contact dermatitis, psoriasis, rheumatoid arthritis, multiplesclerosis, type I diabetes, inflammatory bowel disease, Guillain-Barresyndrome, Crohn's disease, ulcerative colitis, graft versus host disease(and other forms of organ or bone marrow transplant rejection) and lupuserythematosus.

When activation of PKC-theta is implicated in a particular disease,condition, or disorder, the disease, condition, or disorder may also bereferred to as a “PKC-theta-mediated disease” or disease symptom.Accordingly, in another aspect, the present invention provides a methodfor treating or lessening the severity of a disease, condition, ordisorder where activation of PKC-theta is implicated in the diseasestate.

In one embodiment, the invention provides a method of treatingrheumatoid arthritis, comprising administering an effective amount of acompound of general formula I (and subsets as described above andherein) to a subject in need thereof.

In another embodiment, the invention provides a method of treatingmultiple sclerosis, comprising administering an effective amount ofcompounds of general formula I (and subsets thereof as described herein)to a subject in need thereof. The manifestation of MS is variable andthe clinical course of MS can be grouped into four categories:relapsing-remitting, primary progressive, secondary progressive andprogressive-relapsing. The method of the invention can be used to treatMS which presents with each of the recognized clinical courses.Accordingly, a compound of the invention can be administered to apatient with a progressive course of MS to retard or prevent theprogression of neurological impairment. A compound of the invention canalso be administered to a subject with relapsing-remitting, secondaryprogressive or progressive-relapsing MS to inhibit relapse (e.g., anacute attack). For example, a compound of the invention can beadministered to a subject with relapsing-remitting MS during theremitting phase of the disease to prevent or delay relapse.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents which arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

In some embodiments, the compounds of the invention may be employedalone or in combination with other therapeutic agents, particularly,other inhibitors of PKC-theta isoform. Exemplary of these combinationagents include antiproliferative agents (e.g., methotrexate) and theagents disclosed in U.S. Pat. Application Publication No.US2003/0022898, p 14, para. [0173-0174], which is incorporated herein inits entirety. For example, it is expected that a combination therapy forrheumatoid arthritis would involve one or more inventive compounds withmethotrexate. It is understood that other combinations may be undertakenwhile remaining within the scope of the invention.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating implantable medical devices, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device.

Another aspect of the invention relates to inhibiting PKC-theta,activity in a biological sample or a patient, which method comprisesadministering to the patient, or contacting said biological sample witha compound of formula I or a composition comprising said compound. Theterm “biological sample”, as used herein, includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Inhibition of PKC-theta activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, blood transfusion,organ-transplantation, biological specimen storage, and biologicalassays.

Still another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically acceptable carriers to treat states,disorders, symptoms and diseases where PKC-theta isoform plays a role.

EXAMPLES

The following abbreviations are used in the examples:

RT room temperature NMR nuclear magnetic resonance spectroscopy LC-MSliquid chromatography/mass spectrometry HCl hydrochloric acid sat. NaCla saturated solution of sodium chloride NaHCO₃ sodium bicarbonateNaBH₃CN sodium cyanoborohydride NaBH(OAc)₃ sodium triacetoxy borohydrideCH₂Cl₂ methylene chloride EtOAc ethyl acetate DMSO dimethyl sulfoxideTHF tetrahydrofuran MeOH methanol CD₃OD deuterated methanol CDCl₃deuterated chloroform DMSO-d₆ deuterated dimethyl sulfoxide BOC (Boc orboc) tertiary butoxy carbonyl EDC ethyldimethylaminopropyl carbodiimidemL milliliter mmol millimole

A: General Experimental Procedures

Procedure A (Suzuki Coupling of 2,4 Dichloropyrimidine with ArylboronicAcid):

Dissolve 2.57 g (17.3 mmol) of 2,4 dichloropyrimidine and 1.2 eq of a3-substituted phenylboronic acid in 300 mL of THF. Add 2.4 eq. of K₂CO₃and 30 mL of water and flush the flask with nitrogen. Add 1 g ofPd(PPh₃)₄ and heat the mixture to 65° C. for 4 hours. Remove the THF byrotary evaporation and partition the residue between ethyl acetate andwater. Wash the organic layer with a saturated solution of sodiumchloride and remove the solvent. Chromatograph the residue on silicagel, typically using 30% ethyl acetate in hexanes as eluent. Yields aretypically 30-70%.

Procedure B (Reductive Amination of Aryl Aldehyde):

Dissolve 10 mmol of the appropriate aldehyde in 100 mL of CH₂Cl₂. Add1.1 eq. of an appropriately substituted amine, followed by 1.5 eq. ofNaBH(OAc)₃. Stir the mixture at room temperature for two hours and workup by partitioning the reaction mixture between CH₂Cl₂ and water. Washthe organic layer with water followed by a saturated solution of NaCl.Remove the solvent to give product, which is typically >90% pure and isused without purification.

Procedure C (Reductive Amination of Acetophenone):

Dissolve 10 mmol of the appropriate ketone in 100 mL of toluene. Add 1.3eq of an appropriately substituted amine and heat to reflux for fourhours, using a Dean Stark trap to remove water formed in the reaction.Remove the toluene by rotary evaporation and take up the residue in THF.Add NaBH₄ (1.4 eq) portionwise and stir at room temperature for 1 hour.Remove the THF by rotary evaporation and partition the residue betweenethyl acetate/water. Wash the organic layer with a saturated solution ofNaCl and remove the solvent. Chromatograph the residue on silica gel(15% methanol in ethyl acetate) to give the product. Typical yields are20-30%.

Procedure D (Acylation):

Dissolve the amine in methylene chloride. Add 1.2 eq. of triethylaminefollowed by 1.2 eq. of sulfonyl chloride or acid chloride. Stir at roomtemperature for 4 hours. Pour the mixture into a separatory funnel andwash with 1N HCl, saturated NaHCO₃, and sat. NaCl. Remove the solventand chromatograph the residue on silica gel (ethyl acetate as eluent.)Typical yields are >90%.

Procedure D2 (Alternate Acylation):

Dissolve the amine in methylene chloride. Add 4 eq. ofdiisopropylethylamine followed by 1.1 eq. of carboxylic acid and EDCI.Stir at room temperature overnight. The mixture was washed with water,brine, dried over Na₂SO₄ and subject to chromatography on silica gel orHPLC purification to afford product.

Procedure E (Reductive Amination):

Dissolve product from procedure B or C in methylene chloride and add 1.4equivalents of the appropriate aldehyde or ketone. Add 1.5 equivalentsof NaBH(OAc)₃ and stir at room temperature for two hours. Partition thereaction mixture between ethyl acetate and water. Wash the organic layerwith sat. NaHCO₃, followed by sat NaCl. Remove the solvent and purifythe product by chromatography on silica gel. Typical yields are 70-90%.

Procedure F (Nucleophilic Substitution):

Dissolve the appropriate 2-chloropyrimidine in butanol along with 1.2equivalents of an appropriate amine. Add 1.5 equivalents ofdiisopropylethylamine and heat the mixture to 130° C. overnight. Removethe solvent and chromatograph the residue on silica to give product.Typical yields are 70-90%.

Procedure G (BOC Deprotection):

Dissolve the appropriate BOC protected amine (1 mmol) in 20 mL ofmethylene chloride. Add 10 mL of trifluoroacetic acid and stir at roomtemperature for 2 hours. Remove the methylene chloride/trifluoroaceticacid by rotary evaporation, add 5 mL of toluene, and again remove thesolvent to remove residual trifluoroacetic acid. Dry the sample undervacuum overnight.

Procedure G2 (Alternate BOC Deprotection):

Dissolve the appropriate BOC protected amine (1 mmol) in 10 ml ofacetonitrile. Add 5 ml of 4 N HCl-dioxane solution and stir at roomtemperature for 3 hours. Remove the solvent by rotary evaporation. Drythe sample under vacuum overnight.

Procedure G3 (Cbz Deprotection):

Dissolve the appropriate Cbz protected amine (0.5 mmol) in 3 ml ofmethanol. Add 3 ml of 6N HCl (aq) solution and stir at room temperaturefor 30 min. Remove the solvent by rotary evaporation. Dry the sampleunder vacuum overnight.

Procedure H (Suzuki Coupling with 3-Nitrophenylboronic Acid):

Dissolve 5.1 g (35 mmol) of 2,4 dichloropyrimidine and 1.2 eq of a3-nitrophenylboronic acid in 600 mL of THF. Add 2.4 eq. of K₂CO₃ and 60mL of water and flush the flask with nitrogen. Add 2 g of Pd(PPh₃)₄ andheat the mixture to 70° C. for 4 hours. Remove the THF by rotaryevaporation and partition the residue between ethyl acetate and water.Wash the organic layer with a saturated solution of sodium chloride andevaporate the solvent to about 100 mL. By this point the product willprecipitate and can be isolated by filtration. The solid is washed with100 mL of diethyl ether and dried under vacuum to give 6 g (83%) of thedesired product.

Procedure I (Nitro Group Reduction):

The product from above is suspended in 300 mL of ethanol along with 0.7g of 10% Pt/C. The flask is evacuated to remove oxygen and hydrogenintroduced (H₂ atmosphere maintained using a balloon.) The mixture isstirred overnight, by which point the starting nitro compound has goneinto solution and been reduced to the aniline. The mixture is filteredthrough Celite and the solvent evaporated to give a quantitative yieldof product.

Procedure J (Reductive Amination with NaBH₃CN):

An appropriate amine is dissolved in methanol and an appropriatealdehyde or ketone (1.2 equivalents) is added followed by sodiumcyanoborohydride (1.2 equivalents). The pH is adjusted to 6.0 withacetic acid and the mixture stirred overnight. The methanol is removedby rotary evaporation and the residue partitioned between ethyl acetateand water. The organic layer is washed with water followed by saturatedNaCl and the solvent removed. The residue is chromatographed on silicato give product. Typical yields are about 60%.

Procedure K (Acylation Using RCOOH/EDC):

The amine is dissolved in pyridine (10 mL/mmol) along with 1.2equivalents of the appropriate carboxylic acid and 1.2 equivalents ofethyl-dimethylaminopropyl carbodiimide (EDC.) The mixture is stirred atroom temperature overnight and the pyridine removed by rotaryevaporation. The residue is partitioned between ethyl acetate and waterand the organic layer washed with sat. NaCl. Removal of the solventfollowed by chromatography on silica gel (1:1 ethyl acetate:hexaneeluent) yields product, typically in 60-90% yield.

Procedure L (Cyclization Using Mitsunobu Reaction):

Dissolve the amino alcohol in tetrahydrofuran (THF). Triphenylphosphine(1.3 eq.) and N,N-diisopropylethylamine (1.2 eq.) were added, followedby diisopropyl azodicarboxylate (1.3 eq.). The mixture is stirred atroom temperature overnight. Removal of the solvent followed bychromatography on silica gel (2:98 methanol:methylene chloride eluent)yields product.

Procedure M (Suzuki Coupling of 2,4-Dichloro-5-Fluoropyrimidine andBoronic Acid):

Dissolve 10 g (60 mmol) of 2,4-dichloro-5-fluoropyrimidine and 1.0 eq.of 3-formylbenzeneboronic acid in 250 mL of THF. Add 2.0 eq. of K₂CO₃and 250 mL of water and flush the flask with argon. Add 3.5 g (3.0 mmol)of Pd(PPh₃)₄ and heat the mixture to 75° C. for 16 hours. Pour thereaction mixture into a separatory funnel and remove the water layer.Remove the THF by rotary evaporation and add ethyl acetate (ca. 100 mL)to the crude material. The resulting suspension is isolated by vacuumfiltration and washed with ethyl acetate (2×50 mL) to provide an offwhite solid. Yields are typically 50-60%.

Procedure N (Reductive Amination with NaBH(OAc)₃):

Dissolve 1.8 g (7.7 mmol) of the aryl aldehyde in 25 mL of THF. Add 1.2eq. of either 4-amino-1-N-boc-piperidine or N-(3′-aminopropyl) carbamicacid tert-butyl ester and 4 eq. of acetic acid and stir the reactionmixture at rt for 2.5 h. Cool to 0° C. and add 3 eq. of NaBH(OAc)₃. Warmthe reaction mixture to rt and stir for two hours. Work up bypartitioning the reaction mixture between EtOAc and water. Wash theorganic layer with a saturated solution of NaHCO₃ and brine. Remove thesolvent and chromatograph the residue on silica gel (1-5% MeOH/CH₂Cl₂)to obtain a dark yellow oil. Yields are 55-75% for the piperidine adductand 66% for the propylamine compound.

Procedure O (Mesylation):

Dissolve 0.6 g (1.4 mmol) of the amine in 6 mL of methylene chloride.Add 2.0 eq. of diisopropyl ethylamine. Cool to 0° C. and add 1.2 eq. ofmethanesulfonyl chloride dropwise (ca. 1 min) and stir for 5 min. Warmto rt and stir for an additional 1.5 h. Work up by adding a saturatedsolution of NaHCO₃ and extracting with EtOAc. Wash the organic layerwith HCl (1 N) followed by NaHCO₃ and brine. Remove the solvent toafford a crude dark yellow oil. Recrystallization of the piperidinederivative from butanol provides the desired product as a yellow solid(0.34 g, 50% yield). Purification of the propylamine derivative bychromatography on silica gel (100% EtOAc) affords the desired product asa dark yellow oil (0.97 g, 66%).

Procedure P (Reductive Amination):

Dissolve the product from procedure B in CH₂Cl₂. Add 1.2 eq. ofacetaldehyde and 4.0 eq. of acetic acid and stir the reaction mixture atrt for 2.5 h. Cool to 0° C. and add 3 eq. of NaBH(OAc)₃. Warm thereaction mixture to rt and stir for two hours. Work up by partitioningthe reaction mixture between EtOAc and water. Wash the organic layerwith a saturated solution of NaHCO₃ and brine. Remove the solvent andchromatograph the residue on silica gel (1-5% MeOH, CH₂Cl₂), yields are48% for the piperidine adduct and 40% for the propylamine compound.

Procedure Q (Nucleophilic Substitution):

Dissolve the appropriate 2-chloropyrimidine in butanol along with 3equivalents of an appropriate amine. Add 6 equivalents ofdiisopropylethylamine and heat the mixture to 130° C. overnight. Removethe solvent and chromatograph the residue on silica to give product.Typical yields are 40-80%.

Procedure R (BOC Deprotection):

Dissolve the appropriate BOC protected amine (0.4 mmol) in 3 mL ofmethylene chloride. Add 1 mL of trifluoroacetic acid and stir at roomtemperature for 2 hours. Remove the methylene chloride/trifluoroaceticacid by rotary evaporation. Add 5 mL of toluene, and again remove thesolvent to remove residual trifluoroacetic acid (repeat 2 more times).Dry the sample under vacuum overnight.

Procedure S: Synthesis of the Wittig Salt:

Step 1: Dissolve 28.3 g (112 mmol) of iodine and 30.5 g (116 mmol) oftriphenylphosphine in 450 mL of benzene and stir at rt for 5 min. Add18.1 mL (223 mmol) of pyridine and 20 g (93 mmol) of N-Boc-4-piperidinemethanol and reflux the reaction mixture at for 2 h. Cool to rt andfilter off the solid precipitate. Remove the solvent by rotaryevaporation and add hexanes to precipitate the triphenylphosphine oxide.Filter off the oxide and remove the solvent to afford the desired iodideas a faint yellow oil (100% yield) and use in the next step withoutfurther purification.

Step 2: Dissolve the iodide (22.5 g, 69.2 mmol) in acetonitrile (275 mL)and add 2.1 eq. of triphenylphosphine. Reflux the mixture for 18-24 h.Cool to rt and remove the solvent by rotary evaporation. Recrystallizethe residue from ethanol/hexanes. Yields are typically 70-80%.

Procedure T (Wittig Reaction):

To a suspension of the Wittig salt (18.9 g, 32.2 mmol) in THF (125 mL)cooled to 0° C. add 34.2 mL (34.2 mmol) of potassium tert-butoxide (1 Min 2-methyl-2-propanol) dropwise (ca. 1 min) and stir the resultingyellow solution for 15 min. Add a solution of the aryl aldehyde (2.53 g,10.7 mmol) in THF (30 mL) via syringe and warm the resulting purplereaction mixture to rt. After 30 min, quench the reaction with asaturated solution of ammonium chloride and extract with EtOAc. Removethe solvent and chromatograph the residue on silica gel (25%EtOAc/hexanes) to obtain a clear, colorless oil. Yields are typically55-75%.

Procedure U (Olefin Reduction):

Dissolve 1.3 g (3.1 mmol) of the olefin from Procedure G in methanol andadd 5 mol % (0.31 g) of 10% Pt/C. Purge the reaction mixture with argonand affix a balloon of hydrogen. Stir at rt for 2 h. Filter the reactionmixture through celite and wash with methylene chloride. Remove thesolvent and chromatograph (10-25% EtOAc/hexanes) the resulting blackresidue on silica gel to obtain a clear, colorless oil. Yields aretypically 85%-95%.

Procedure V: (Suzuki Coupling with Thiophene Boronic Acid):

Dissolve 0.43 g (2.9 mmol) of 2,4 dichloropyrimidine and 1.1 eq of5-formyl-2-thiopheneboronic acid in 10 mL of THF. Add 2.0 eq. of K₂CO₃and 10 mL of water and flush the flask with nitrogen. Add 0.17 g ofPd(PPh₃)₄ and heat the mixture to 75° C. for 12 hours. Remove the waterlayer and concentrate the TI-IF layer by rotary evaporation.Chromatograph the residue quickly on silica gel, typically using 75%ethyl acetate in hexanes as eluent. Yield: 23%.

B. Synthesis of Exemplary Intermediates and Compounds:

Intermediate 1: 3-(2-Chloro-pyrimidin-4-yl)-benzaldehyde: 2,4dichloropyrimidine and 3-formyl phenyl boronic acid were coupledfollowing procedure A. The yield was 60%. LC-MS showed the productwas >95% pure and had the expected M+H⁺ of 219. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ10.1 (s, 1H)8.7 (d, 1H) 8.6 (m, 1H) 8.4 (m, 1H) 8.1 (m, 1H) 7.7 (m, 2H).

Intermediate 2:{3-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-propyl}-carbamic acidtert-butyl ester: The product from the above reaction and tert-butylN-(3-aminopropyl)carbamate) were coupled by procedure B. The yield was85%. LC-MS showed the product had the expected M+H⁺ of 377.

Intermediate 3:(3-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-propyl)-carbamicacid tert-butyl ester: The product from the above reaction was coupledwith acetaldehyde by procedure B. The yield was 80%. LC-MS showed theproduct had the expected M+H⁺ of 405.

Compound 1:(4-{2-[4-(3-{[(3-Amino-propyl)-ethyl-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol):Intermediate 3 from above was coupled with tyramine following procedureF. The product was deprotected by procedure G. LC-MS showed the producthad the expected M+H⁺ of 406. ¹H NMR (Varian 300 MHz, DMSO-d₆, shiftsrelative to the solvent peak at 2.49 ppm) δ 8.5 (s, 1H) 8.4 (d, 1H) 8.2(s, 1H) 8.1 (m, 3H), 7.9 (d, 1H) 7.6 (m, 1H) 7.4 (s, 1H) 7.0 (d, 2H) 6.6(d, 2H) 4.4 (s, 2H) 3.6 (m, 2H) 3.5 (s, 1H) 3.1 (m, 4H) 2.8 (m, 4H) 2.1(m, 2H) 1.3 (m, 3H).

Intermediate 4:(3-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-propyl)-carbamicacid tert-butyl ester. Intermediate 2 from above was treated withmethanesulfonyl chloride following procedure D. LC-MS showed the producthad the expected M+H⁺ of 456.

Compound 2:N-(3-Amino-propyl)-N-(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 from above was coupled with tyramine following procedureF and the resulting product deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 456. ¹H NMR (Varian 300 MHz,DMSO-d₆, shifts relative to the solvent peak at 2.49 ppm) δ 8.5 (d, 1H)8.1 (m, 2H) 8.0 (s, 2H) 7.6 (m, 2H) 7.4 s, 1H) 7.0 (d, 2H) 6.7 (d, 2H)4.5 (s, 2H) 3.6 (m, 2H) 3.2 (m, 2H) 3.0 (s, 3H) 2.8 (m, 2H) 2.7 (m, 2H)1.8 (m, 2H).

Compound 3:N-(4-{2-[4-(3-{[(3-Amino-propyl)-methanesulfonyl-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenyl)-acetamide:Intermediate 4 from above was coupled withN-[4-(2-Amino-ethyl)-phenyl]-acetamide by procedure F and the resultingproduct deprotected by procedure G to give 3. LC-MS showed the producthad the expected M+H⁺ of 497. ¹H NMR (Varian 300 MHz, CDCl₃-CD₃OD,shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 8.0 (m,1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.3 (m, 1H) 7.2 (d, 2H) 4.4 (s,2H) 3.9 (m, 2H) 3.3 (m, 2H) 2.9 (m, 2H) 2.8 (s, 3H) 2.7 (m, 2H) 2.1 (s,3H) 1.8 (m, 2H).

Compound 4:N-(4-{2-[4-(3-{[(3-Amino-propyl)-methanesulfonyl-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenyl)-methanesulfonamide:intermediate 4 from above was coupled withN-[4-(2-Amino-ethyl)-phenyl]-methanesulfonamide following procedure Fand the resulting product deprotected following procedure G to give 4.LC-MS showed the product had the expected M+H⁺ of 533. ¹H NMR (Varian300 MHz, CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm) δ8.0 (m, 2H) 7.9 (d, 1H) 7.6 (d, 1H) 7.4 (m, 1H) 7.3 (m, 1H) 7.1 (d, 2H)7.0 (d, 2H) 4.4 (s, 2H) 3.9 (m, 2H), 3.2 (m, 5H) 2.9 (m, 2H) 2.8 (s, 3H)2.7 (m, 4H) 1.7 (m, 2H).

Compound 5:N-(3-{2-[2-(4-Amino-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-(3-amino-propyl)-methanesulfonamide:Intermediate 4 from above was coupled with 4-(2-Amino-ethyl)-phenylaminefollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 455.CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m,2H) 7.9 (d, 1H) 7.5 (d, 1H) 7.4 (m, 1H) 7.2 (m, 3H) 7.1 (d, 2H) 4.4 (s,2H) 3.7 (m, 2H) 3.2 (m, 4H) 2.9 (m, 2H) 2.8 (s, 3H) 2.6 (m, 2H) 1.6 (m,2H).

Compound 6:N-(3-Amino-propyl)-N-(3-{2-[2-(3,4-dihydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 from above was coupled with4-(2-Amino-ethyl)-benzene-1,2-diol following procedure F and theresulting product deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 472. ¹H NMR (Varian 300 MHz,CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m,2H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (m, 1H) 7.2 (m, 1H) 6.7 (d, 1H) 6.6 (m,2H) 4.7 (s, 2H) 3.8 (m, 2H) 3.6 (m, 2H) 2.9 (s, 3H) 2.8 (m, 4H) 1.8 (m,2H).

Compound 7:N-(3-Amino-propyl)-N-[3-(2-{[2-(3,4-dihydroxy-phenyl)-ethyl]-methyl-amino}-pyrimidin-4-yl)-benzyl]-methanesulfonamide:Intermediate 4 from above was coupled with4-(2-Methylamino-ethyl)-benzene-1,2-diol following procedure F and theresulting product deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 486. ¹H NMR (Varian 300 MHz,CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (m,2H) 8.0 (m, 2H) 7.6 (d, 1H) 7.5 (m, 1H) 6.6 (m, 1H) 6.4 (m, 2H) 4.4 (s,2H) 4.0 (m, 2H) 3.2 (m, 5H) 2.9 (s, 3H) 2.8 (m, 4H) 1.7 (m, 2H).

Compound 8:N-(3-Amino-propyl)-N-(3-{2-[2-(3-hydroxy-4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 from above was coupled with5-(2-Amino-ethyl)-2-methoxy-phenol following procedure F and theresulting product deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 486. ¹H NMR (Varian 300 MHz,CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m,2H) 8.0 (d, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.2 (m, 1H) 6.8 (s, 1H) 6.6 (s,2H) 4.5 (s, 2H) 3.8 (m, 2H) 3.7 (s, 3H) 3.3 (m, 2H), 2.9 (m, 7H) 1.8 (m,2H).

Compound 9:N-(3-Amino-propyl)-N-{3-[2-(4-hydroxy-benzylamino)-pyrimidin-4-yl]-benzyl}-methanesulfonamide:Intermediate 4 from above was coupled with 4-aminomethyl-phenolfollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 442.

Compound 10:4-{2-[4-(3-{[(3-Amino-propyl)-methanesulfonyl-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-benzenesulfonamide:Intermediate 4 was coupled with 4-(2-Amino-ethyl)-benzenesulfonamidefollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 519. ¹HNMR (Varian 300 MHz, CDCl₃-CD₃OD, shifts relative to the solvent peak at7.24 ppm) δ 8.0 (m, 2H) 7.8 (m, 1H) 7.6 (m, 4H) 7.4 (m, 1H) 7.2 (m, 2H)4.3 (s, 2H) 3.8 (m, 2H) 3.4 (m, 2H) 2.9 (m, 2H) 2.8 (s, 3H) 2.6 (m, 2H)1.6 (m, 2H).

Compound 11:N-(3-Amino-propyl)-N-(3-{2-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled with 3-(2-Amino-1-hydroxy-ethyl)-phenolfollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 472. ¹HNMR (Varian 300 MHz, CDCl₃-CD₃OD, shifts relative to the solvent peak at7.24 ppm) δ 8.1 (m, 2H) 7.9 (m, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.3 (m, 1H)7.0 (m, 1H) 6.8 (m, 2H) 6.6 (m, 1H) 4.8 (m, 1H) 4.4 (s, 2H) 3.8 (m, 2H)3.3 (m, 2H) 2.9 (s, 3H) 2.7 (m, 2H) 1.7 (m, 2H).

Compound 12:N-(3-Amino-propyl)-N-{3-[2-(2-pyridin-4-yl-ethylamino)-pyrimidin-4-yl]-benzyl}-methanesulfonamide:Intermediate 4 was coupled with 2-pyridin-4-yl-ethylamine followingprocedure F and the resulting product deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 441. ¹H NMR (Varian300 MHz, CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm) δ8.6 (m, 2H) 8.3 (m, 1H) 8.1 (m, 3H) 7.9 (m, 1H) 7.6 (m, 1H) 7.5 (m, 1H)7.3 (m, 1H) 4.4 (m, 2H) 4.0 (m, 2H) 3.3 (m, 2H) 2.9 (m, 4H) 1.8 (m, 2H).

Compound 13:N-(3-Amino-propyl)-N-(3-{2-[2-(4-hydroxy-3,5-dimethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled with 4-(2-Amino-ethyl)-2,6-dimethoxy-phenolfollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 516. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.26 (d, 1H) 8.21 (s, 1H) 8.12 (d, 1H) 7.68 (d, 1H) 7.58 (d, 1H)7.33 (d, 1H) 6.53 (s, 2H) 4.50 (s, 2H) 3.76 (s, 6H) 3.37 (m, 2H) 2.97(s, 3H) 2.9 (m, 2H) 2.81 (m, 2H) 1.70 (m, 2H).

Compound 14:N-(3-Amino-propyl)-N-[3-(2-phenethylamino-pyrimidin-4-yl)-benzyl]methanesulfonamide:Intermediate 4 was coupled to phenethylamine following procedure F andthe resulting product deprotected following procedure G. LC-MS showedthe product had the expected M+H⁺ of 440. ¹H NMR (Varian 300 MHz,CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m,3H) 7.7 (m, 1H) 7.5 (m, 2H) 7.2 (m, 5H) 4.5 (d, 2H) 3.8 (m, 2H) 3.6 (m,1H) 3.3 (m, 3H) 3.0 (m, 2H) 2.9 (s, 3H) 1.8 (m, 2H).

Compound 15:N-(3-Amino-propyl)-N-(3-{2-[2-(4-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled with 2-(4-fluoro-phenyl)-ethylamine followingprocedure F and the resulting product deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 458. ¹H NMR (Varian300 MHz, CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm) δ8.1 (m, 3H) 7.7 (m, 1H) 7.5 (m, 2H) 7.2 (m, 2H) 6.9 (m, 2H) 4.5 (s, 2H)3.8 (m, 2H) 3.7 (m, 1H) 3.4 (m, 2H) 2.9 (m, 7H) 1.9 (s, 2H).

Compound 16:N-(3-Amino-propyl)-N-{3-[2-(4-hydroxy-3-methoxy-benzylamino)-pyrimidin-4-yl]-benzyl}-methanesulfonamide:Intermediate 4 was coupled with 4-Aminomethyl-2-methoxy-phenol followingprocedure F and the resulting product deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 472. ¹H NMR (Varian300 MHz, CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm) δ8.2 (m, 3H) 7.6 (m, 2H) 7.3 (m, 2H) 6.8 (m, 2H) 4.4 (s, 2H) 3.8 (s, 2H)3.7 (m, 2H) 3.4 (s, 3H) 2.9 (s, 3H) 2.8 (m, 2H) 1.7 (m, 2H).

Compound 17:N-(3-Amino-propyl)-N-(3-{2-[2-(1H-indol-3-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled with 2-(1H-Indol-3-yl)-ethylamine followingprocedure F and the resulting product deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 479. ¹H NMR (Varian300 MHz, CDCl₃-CD₃OD, shifts relative to the solvent peak at 7.24 ppm)8.1 (m, 2H) 7.9 (m, 1H) 7.7 (d, 1H) 7.6 (m, 4H) 7.2 (m, 1H) 7.0 (m, 2H)4.4 (d, 2H) 3.9 (m, 1H) 3.6 (m, 1H) 3.3 (m, 2H) 3.1 (m, 2H) 2.9 (m, 5H)1.7 (m, 2H).

Compound 18:N-(3-Amino-propyl)-N-(3-{2-[2-(6-fluoro-1H-indol-3-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled with 2-(6-Fluoro-1H-indol-3-yl)-ethylaminefollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 497. ¹HNMR (Varian 300 MHz, CDCl₃-CD₃OD, shifts relative to the solvent peak at7.24 ppm) δ 8.1 (m, 2H) 7.8 (d, 1H) 7.5 (m, 4H) 7.3 (m, 1H) 6.8 (m, 2H)4.4 (d, 2H) 3.9 (m, 1H) 3.6 (m, 2H) 3.3 (m, 2H) 3.1 (m, 1H) 2.8 (m, 5H)1.7 (m, 2H).

Compound 19:{3-[(3-{2-[2-(4-Hydroxy-3-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-carbamicacid tert-butyl ester: Intermediate 4 was coupled to4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showedthe product had the expected M+H⁺ of 586. ¹H NMR (Varian 300 MHz, CDCl₃,shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (s, 1H) 8.05 (s,1H) 7.96 (s, 1H) 7.50 (m, 2H) 7.0 (m, 1H) 6.83 (m, 1H) 6.77 (m, 2H) 5.64(s, 1H) 4.84 (s, 1H) 4.44 (s, 3H) 4.09 (s, 2H) 3.86 (s, 2H) 3.77 (m, 1H)3.25 (m, 3H) 3.07 (br s, 2H) 2.90 (m, 2H) 2.85 (S, 3H) 1.60 (m, 2H) 1.39(s, 9H).

Compound 20:N-(3-Amino-propyl)-N-(3-{2-[2-(4-hydroxy-3-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Compound 19 was deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 486.

Compound 21:N-(3-Amino-propyl)-N-{3-[2-(2-p-tolyl-ethylamino)-pyrimidin-4-yl]-benzyl}-methanesulfonamide:Intermediate 4 was coupled to 2-p-tolyl-ethylamine following procedure Fand the resulting product deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 454. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 9.55 (br s,1H) 8.1 (m, 2H) 7.6 (m, 4H) 7.2 (m, 4H) 4.4 (s, 2H) 3.81 (s, 2H) 3.37(m, 2H) 2.97 (m, 4H) 2.94 (s, 3H) 2.25 (s, 3H) 1.75 (s, 2H) 1.69 (m,2H).

Compound 22:N-(3-Amino-propyl)-N-(3-{2-[2-(4-hydroxy-3-nitro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled to 4-(2-Amino-ethyl)-2-nitro-phenol byprocedure F and the resulting product deprotected by procedure G2. LC-MSshowed the product had the expected M+H⁺ of 501. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.4 (s, 1H)8.3 (d, 1H) 8.2 (d, 1H) 8.0 (s, 1H) 7.8 (d, 1H) 7.6 (m, 3H) 7.0 (m, 1H)4.5 (s, 2H) 4.0 (m, 2H) 3.4 (m, 2H) 3.0 (m, 5H) 2.8 (m, 2H) 1.8 (m, 2H).

Compound 23:{3-[(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-carbamicacid tert-butyl ester: Intermediate 4 was coupled to intermediate 71following procedure F. LC-MS showed the product had the expected M+H⁺ of590. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.3 (m, 1H) 8.1 (d, 1H) 8.0 (d, 1H) 7.5 (m, 4H) 7.1 (m,2H) 6.9 (m, 1H) 4.9 (m, 1H) 4.5 (s, 2H) 3.8 (m, 2H) 3.5 (s, 1H) 3.3 (m,2H) 3.1 (m, 2H) 2.9 (m, 5H) 1.6 (m, 2H) 1.4 (s, 9H).

Compound 24:N-(3-Amino-propyl)-N-(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Compound 23 was deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 490. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.30 ppm) δ 8.3 (m, 2H) 8.2 (d,1H) 7.8 (d, 1H) 7.6 (m, 1H) 7.5 (d, 1H) 7.3 (s, 1H) 7.1 (d, 1H) 6.8 (d,1H) 4.6 (s, 2H) 3.9 (m, 2H) 3.4 (m, 2H) 3.0 (s, 3H) 2.9 (m, 4H) 1.8 (m,2H).

Compound 25:{3-[(3-{2-[2-(3-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-carbamicacid tert-butyl ester: Intermediate 4 was coupled with3-(2-amino-ethyl)-phenol following procedure F. LC-MS showed the producthad the expected M+H⁺ of 556. ¹H NMR (Varian 300 MHz, CDCl₃, shiftsrelative to the solvent peak at 7.24 ppm) δ 8.3 (m, 2H) 7.9 (d, 1H) 7.5(m, 2H) 7.2 (m, 1H) 7.0 (d, 1H) 6.8 (m, 3H) 4.9 (s, br, 1H) 4.5 (s, 2H)3.8 (m, 2H) 3.3 (m, 2H) 3.1 (m, 2H) 2.9 (m, 5H) 1.7 (m, 2H) 1.4 (s, 9H).

Compound 26:N-(3-Amino-propyl)-N-(3-{2-[2-(3-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Compound 25 was deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 456. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.30 ppm) δ 8.3 (m, 2H) 8.2 (d,1H) 7.8 (d, 1H) 7.6 (m, 1H) 7.5 (d, 1H) 7.1 (m, 1H) 6.8 (m, 2H) 6.6 (d,1H) 4.6 (s, 2H) 3.9 (m, 2H) 3.4 (m, 2H) 3.0 (m, 5H) 2.8 (m, 2H) 1.8 (m,2H).

Compound 27:N-(3-Amino-propyl)-N-(3-{2-[2-(2-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled with 2-(2-amino-ethyl)-phenol followingprocedure F and the resulting product deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 456. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.3(m, 3H) 7.8 (d, 1H) 7.6 (m, 1H) 7.5 (d, 1H) 7.1 (d, 1H) 7.0 (m, 1H) 6.7(d, 2H) 4.5 (s, 2H) 3.9 (m, 2H) 3.4 (m, 2H) 3.0 (m, 5H) 2.8 (m, 2H) 1.8(m, 2H).

Compound 28:{3-[Methanesulfonyl-(3-{2-[2-(3,4,5-trihydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-amino]-propyl}-carbamicacid tert-butyl ester: Intermediate 4 was coupled with5-(2-Amino-ethyl)-benzene-1,2,3-triol following procedure F. LC-MSshowed the product had the expected M+H⁺ of 588. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (m, 2H)8.0 (m, 1H) 7.6 (m, 2H) 7.3 (m, 3H) 4.8 (m, 1H) 4.5 (s, 2H) 3.9 (m, 2H)3.3 (m, 2H) 3.0 (m, 2H) 2.9 (m, 5H) 1.6 (m, 2H) 1.4 (s, 9H).

Compound 29:N-(3-Amino-propyl)-N-(3-{2-[2-(3,5-dichloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled to 4-(2-Amino-ethyl)-2,6-dichloro-phenol byprocedure F and the resulting product was deprotected by procedure G.LC-MS showed the product had the expected M+H⁺ of 524. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.4(m, 2H) 8.2 (d, 1H) 7.8 (d, 1H) 7.2 (s, 2H) 4.6 (s, 2H) 3.9 (m, 2H) 3.4(m, 2H) 3.0 (s, 3H) 2.9 (m, 2H) 2.8 (m, 2H) 1.8 (m, 2H).

Compound 30:N-(3-Amino-propyl)-N-(3-{2-[2-(3-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled to 2-(3-Chloro-phenyl)-ethylamine followingprocedure F and the resulting product deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 474. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.85(m, 1H) 8.15 (m, 4H) 7.6 (m, 6H) 4.45 (s, 2H) 3.95 (m, 2H) 3.4 (m, 2H)3.18 (m, 4H) 3.0 (m, 2H) 2.9 (s, 3H) 1.75 (m, 2H).

Compound 31:N-(3-Amino-propyl)-N-(3-{2-[2-(2-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled to 2-(2-chloro-phenyl)-ethylamine followingprocedure F and the resulting product deprotected by procedure G. LC-MSshowed the product had the expected M+H⁺ of 474. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.8 (m, 1H)8.18 (m, 4H) 7.6 (m, 6H) 4.45 (s, 2H) 3.95 (m, 2H) 3.4 (m, 2H) 3.18 (m,4H) 3.0 (m, 2H) 2.9 (s, 3H) 1.75 (m, 2H).

Compound 32:N-(3-Amino-propyl)-N-(3-{2-[2-(4-chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled to 2-(4-chloro-phenyl)-ethylamine followingprocedure F and the resulting product deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 474. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.7(m, 1H) 8.16 (m, 4H) 7.65 (m, 6H) 4.45 (s, 2H) 3.95 (m, 2H) 3.4 (m, 2H)3.18 (m, 4H) 3.0 (m, 2H) 2.9 (s, 3H) 1.75 (m, 2H).

Compound 33:N-(3-Amino-propyl)-N-(3-{2-[2-(3-hydroxy-4-nitro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled with 5-(2-amino-ethyl)-2-nitro-phenol and theresulting product deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 501. ¹H NMR (Varian 300 MHz, DMSO-d₆,shifts relative to the solvent peak at 2.49 ppm) δ 8.4 (d, 1H) 8.1 (m,2H) 7.8 (m, 4H) 7.6 (s, 1H) 7.3 (m, 1H) 7.1 (s, 1H) 6.9 (d, 1H) 4.4 (s,2H) 3.7 (m, 2H) 3.6 (s, 1H) 3.2 (m, 2H) 3.0 (s, 3H) 2.9 (m, 2H) 2.7 (m,2H) 1.7 (m, 2H).

Compound 34:N-(3-Amino-propyl)-N-(3-{2-[2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 4 was coupled to 5-(2-Amino-ethyl)-3H-benzooxazol-2-onefollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 497. ¹HNMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solvent peak at2.49 ppm) δ 11.6 (s, 1H) 8.5 (d, 1H) 8.1 (m, 2H) 7.9 (m, 2H) 7.6 (m, 1H)7.4 (m, 1H) 7.0 (m, 3H) 4.4 (s, 2H) 3.7 (m, 2H) 3.2 (m, 2H) 3.0 (s, 3H)2.9 (m, 2H) 2.7 (m, 2H) 1.7 (m, 2H).

Compound 35:{3-[(3-{2-[2-(3-Bromo-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-carbamicacid tert-butyl ester: Intermediate 4 was coupled to4-(2-amino-ethyl)-2-bromo-phenol following procedure F. LC-MS showed theproduct had the expected M+H⁺ of 634. ¹H NMR (Varian 300 MHz, CDCl₃,shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H) 8.1 (m,1H) 8.0 (d, 1H) 7.5 (m, 3H) 7.4 (s, 1H) 7.1 (m, 2H) 6.9 (d, 1H) 4.9 (m,1H) 4.5 (s, 2H) 3.8 (m, 2H) 2.9 (m, 5H) 1.6 (m, 2H) 1.4 (s, 9H).

Compound 36:N-(3-Amino-propyl)-N-(3-{2-[2-(3-bromo-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Compound 35 was deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 534. ¹H NMR (Varian 300 MHz, DMSO-d₆,shifts relative to the solvent peak at 2.49 ppm) δ 8.4 (d, 1H) 8.1 (m,2H) 7.8 (m, 2H) 7.6 (m, 2H) 7.4 (s, 1H) 7.3 (m, 1H) 7.1 (d, 1H) 6.9 (d,1H) 4.4 (s, 2H) 3.4 (m, 2H) 3.2 (m, 2H) 3.0 (s, 3H) 2.8 (m, 2H) 2.7 (m,2H) 1.7 (m, 2H).

Intermediate 5: 2-Chloro-4-(3-nitro-phenyl)-pyrimidine: 2,4dichloropyrimidine was coupled to 3-nitrophenyl boronic acid followingprocedure A. The workup and purification protocol was modified asfollows: The THF was removed from the reaction mixture by rotaryevaporation and the residue taken up in ethyl acetate. The solution waswashed with water followed by sat. NaCl and the organic layerconcentrated by rotary evaporation until the product started toprecipitate, at which point the flask was placed in an ice bath for twohours. The product was collected by filtration in a Buchner funnel. Theyield was 60%. Product was >95% pure by LC-MS and showed the expectedM+H⁺ of 236.

Intermediate 6: 3-(2-Chloro-pyrimidin-4-yl)-phenylamine: Intermediate 5was dissolved in ethanol along with 5 mol % of 5% Pt/C. The mixture wasstirred under an atmosphere of H₂ for 24 hours and then filtered througha pad of Celite to remove catalyst. Removal of the solvent gave productin 90% yield. LC-MS showed purity >95% and the expected M+H⁺ of 206.

Intermediate 7:4-[3-(2-Chloro-pyrimidin-4-yl)-phenylamino]-piperidine-1-carboxylic acidtert-butyl ester: Intermediate 6 was coupled with4-oxo-piperidine-1-carboxylic acid tert-butyl ester by procedure J. Theproduct was purified on silica (1:1 ethyl acetate:hexanes.) Yield: 80%.LC-MS showed purity >95% and the expected M+H⁺ of 389.

Compound 37:4-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenylamino)-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 7 was coupled with tyraminefollowing procedure F. LC-MS showed the product had the expected M+H⁺ of490. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.28 (d, 1H) 7.25 (m, 3H) 7.05 (m, 2H) 6.92 (d, 1H) 6.7(m, 3H) 5.45 (m, 1H) 4.0 (m, 2H) 3.7 (m, 4H) 3.49 (m, 1H) 2.85 (m, 4H)2.45 (t, 2H) 1.5 (s, 9H).

Compound 38:4-(2-{4-[3-(Piperidin-4-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Compound 37 was deprotected by procedure G. LC-MS showed the product hadthe expected M+H⁺ of 390. ¹H NMR (Varian 300 MHz, DMSO-d₆, shiftsrelative to the solvent peak at 2.49 ppm) δ 8.2 (d, 1H) 7.3-7.5 (m, 3H)6.95-7.25 (m, 4H) 6.7 (m, 2H) 5.45 (m, 1H) 3.6-3.9 (m, 3H) 3.45 (m, 2H)3.0-3.25 (m, 4H) 2.9 (m, 2H) 2.4 (m, 2H) 1.95 (m, 2H).

Compound 39:4-(3-{2-[2-(4-Hydroxy-3-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenylamino)-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 7 was coupled with4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showedthe product had the expected M+H⁺ of 520. ¹H NMR (Varian 300 MHz, CDCl₃,shifts relative to the solvent peak at 7.24 ppm) δ 8.30 (d, 1H) 7.25-7.4(m, 3H) 6.8-7.0 (m, 2H) 6.65-6.78 (m, 3H) 5.45 (m, 1H) 4.0 (m, 2H) 3.82(s, 3H) 3.7 (m, 4H) 3.49 (m, 1H) 2.85 (m, 4H) 2.0 (m, 2H) 1.5 (s, 9H).

Compound 40:2-Methoxy-4-(2-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Compound 39 was deprotected by procedure G. LC-MS showed the product hadthe expected M+H⁺ of 420. ¹H NMR (Varian 300 MHz, DMSO-d₆, shiftsrelative to the solvent peak at 2.49 ppm) δ 8.2 (d, 1H) 7.3-7.5 (m, 3H)7.1-7.25 (m, 3H) 7.0 (m, 1H) 6.7 (s, 1H) 4.85 (m, 1H) 3.8 (s, 3H)3.6-3.9 (m, 3H) 3.45 (m, 2H) 3.3 (m, 2H) 3.15-3.25 (m, 2H) 2.9 (m, 2H)2.28 (m, 2H) 1.7 (m, 2H).

Compound 41:{4-[3-(Piperidin-4-ylamino)-phenyl]-pyrimidin-2-yl}-(2-thiophen-2-yl-ethyl)-amine:Intermediate 7 was coupled with 2-thiophen-2-yl-ethylamine by procedureF and the resulting product deprotected by procedure G. LC-MS showed theproduct had the expected M+H⁺ of 380. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.28 (d, 1H) 6.8-7.5(m, 8H) 4.85 (m, 1H) 3.9 (m, 2H) 3.7 (m, 2H) 3.1-3.5 (m, 4H) 2.2-2.3 (m,2H) 2.28 (m, 2H) 1.6-1.8 (m, 2H).

Compound 42:Naphthalen-1-ylmethyl-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 7 was coupled with naphthalen-1-yl-methylamine followingprocedure F and the resulting product deprotected by procedure G. LC-MSshowed the product had the expected M+H⁺ of 410. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H)8.18 (d, 1H) 7.8-8.0 (m, 2H) 7.4-7.7 (m, 7H) 7.32 (m, 1H) 7.0 (m, 1H)5.32 (s, 2H) 4.95 (m, 1 h) 3.58 (m, 1H) 3.2-3.4 (m, 3H) 2.8-3.1 (m, 2H)2.1 (m, 2H) 1.65 (m, 2H).

Compound 43:2-Methoxy-5-(2-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 7 was coupled with 5-(2-Amino-ethyl)-2-methoxy-phenolfollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 420. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.3 (d, 1H) 7.0-7.6 (m, 8H) 4.95 (m, 1H) 3.89 (m, 1H) 3.7 (m, 1H)3.4 (m, 2H) 2.9-3.3 (m, 5H) 2.2-2.3 (m, 2H) 1.95 (m, 2H) 1.6-1.8 (m,2H).

Compound 44:443-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenylamino)-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 7 was coupled with intermediate 71following procedure F. LC-MS showed the product had the expected M+H⁺ of523. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 6.6-7.4 (m, 9H) 5.5 (m, 1H) 4.05 (m, 2H) 3.7 (m, 4H) 3.5(m, 1H) 2.8-3.0 (m, 5H) 1.5 (s, 9H) 1.4 (m, 2H).

Compound 45:2-Chloro-4-(2-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Compound 44 was deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 424. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 6.95-7.5(m, 9H), 6.8 (m, 1H) 4.9 (m, 1H) 3.85 (m, 1H) 3.72 (m, 1H) 3.4-3.5 (m,2H) 3.05-3.2 (m, 3H) 2.9 (m, 2H) 2.25 (m, 2H) 1.6-1.8 (m, 2H).

Compound 46:(2-Benzo[1,3]dioxol-5-yl-ethyl)-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-yl}-amine:Intermediate was coupled with 2-benzo[1,3]dioxol-5-yl-ethylaminefollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 418. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.2 (d, 1H) (6.95-7.5 (m, 7H) 6.68 (m, 2H) 5.8 (s, 2H) 4.95 (m,1H) 3.6-3.9 (m, 4H) 3.4 (m, 2H) 3.15 (m, 2H) 2.25 (m, 3H) 1.7 (m, 2H).

Compound 47:[2-(3-Fluoro-phenyl)-ethyl]-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 7 was coupled with 2-(3-fluoro-phenyl)-ethylamine followingprocedure F and the resulting product deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 393. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2(d, 1H) 6.95-7.6 (m, 8H) 6.9 (m, 1H) 4.95 (m, 1H) 3.6-4.0 (m, 3H) 3.4(m, 3H) 3.15 (m, 2H) 3.0 (m, 2H) 2.25 (m, 2H) 1.7 (m, 2H).

Compound 48:2,6-Dichloro-4-(2-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 7 was coupled with 4-(2-Amino-ethyl)-2,6-dichloro-phenolfollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 458. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.2 (d, 1H) 7.05-7.6 (m, 6H) 7.0 (m, 1H) 4.95 (m, 1H) 3.6-4.0 (m,3H) 3.4 (m, 2H) 3.1-3.2 (m, 2H) 2.8-2.95 (m, 2H) 2.25 (m, 3H) 1.7 (m,2H).

Compound 49:3-(2-{4-[3-(Piperidin-4-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 7 was coupled with 3-(2-amino-ethyl)-phenol followingprocedure F and the resulting product deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 390. ¹H NMR (Varian300 MHz, DMSO-d₆, shifts relative to the solvent peak at 2.49 ppm) δ 8.8(m, 5H) 8.4 (d, 1H) 7.4 (m, 2H) 7.3 (m, 1H) 7.0 (d, 1H) 6.9 (m, 1H) 3.7(m, 2H) 3.4 (m, 1H) 3.1 (m, 2H) 2.9 (m, 3H) 2.1 (m, 1H) 1.8 (m, 2H) 1.5(m, 2H).

Compound 50:2-Bromo-4-(2-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 7 was coupled with 4-(2-Amino-ethyl)-2-bromo-phenolfollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 468. ¹HNMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solvent peak at2.49 ppm) δ 8.8 (m, 5H) 8.4 (d, 1H) 7.4 (m, 2H) 7.3 (m, 1H) 7.0 (d, 1H)6.9 (m, 1H) 3.7 (m, 2H) 3.4 (m, 1H) 3.1 (m, 2H) 2.9 (m, 3H) 2.1 (m, 1H)1.8 (m, 2H) 1.5 (m, 2H).

Compound 51:(6-Fluoro-4H-benzo[1,3]dioxin-8-ylmethyl)-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 7 was coupled withC-(6-fluoro-4H-benzo[1,3]dioxin-8-yl)-methylamine following procedure Fand the resulting intermediate 4eprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 436. ¹H NMR (Varian 300 MHz,DMSO-d₆, shifts relative to the solvent peak at 2.49 ppm) δ 8.6 (s, 1H)8.4 (d, 1H) 8.3 (d, 1H) 7.8 (t, 1H) 7.4 (d, 1H), 7.2 (d, 1H), 7.1 (d,2H), 6.6 (d, 2H), 3.4 (d, 2H), 2.8 (d, 2H).

Compound 52:4-{2-[4-(3-Nitro-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 5 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 337. ¹H NMR (Varian 300 MHz,DMSO-d₆, shifts relative to the solvent peak at 2.49 ppm) (d, 1H)7.6-6.6 (m, 7H) 6.0 (d, 2H) 4.85 (s, 2H) 4.40 (d, 2H) 3.0 (m, 1H), 2.0(m, 4H), 1.6 (m, 4H).

Intermediate 8:3-[3-(2-Chloro-pyrimidin-4-yl)-phenylamino]-piperidine-1-carboxylic acidtert-butyl ester: Intermediate 6 was coupled with3-oxo-piperidine-1-carboxylic acid tert-butyl ester by procedure J. Theproduct was purified on silica (1:1 ethyl acetate:hexanes) Yield: 65%.LC-MS showed the product had the expected M+H⁺ of 389.

Compound 53:4-(2-{4-[3-(Piperidin-3-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 8 was coupled with tyramine following procedure F and theresulting product deprotected by procedure G. LC-MS showed the producthad the expected M+H⁺ of 390. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 6.95-7.6 (m, 8H)6.7 (m, 2H) 4.95 (m, 1H) 3.7-3.9 (m, 2H) 3.5 (m, 1H) 2.8-3.2 (m, 5H)1.6-2.4 (m, 5H).

Compound 54:2-Chloro-4-(2-{4-[3-(piperidin-3-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 8 was coupled with intermediate 71 following procedure Fand the resulting product deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 424. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H)6.95-7.6 (m, 8H) 6.8 (d, 1H) 4.95 (m, 1H) 3.7-3.9 (m, 2H) 3.5 (m, 1H)2.8-3.2 (m, 5H) 1.6-2.3 (m, 5H).

Intermediate 8b:3-[3-(2-Chloro-pyrimidin-4-yl)-phenylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester: Intermediate 6 was coupled with3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester following procedureJ. The product was purified on silica gel using 1:1 ethylacetate:hexanes as eluent. Yield: 70%. LC-MS showed the product had theexpected M+H⁺ of 375.

Compound 55:4-(2-{4-[3-(Pyrrolidin-3-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 8b was coupled with tyramine following procedure F and theresulting product deprotected following procedure G. LC-MS showed theproduct had the expected M+H⁺ of 376. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 7.0-7.5(m, 4H) 6.9 (d, 1H) 6.68 (d, 2H) 5.05 (m, 1H) 4.28 (m, 1H) 3.8 (m, 2H)3.2-3.6 (m, 4H) 2.9 (m, 2H) 2.0-2.6 (m, 2H).

Compound 56:N-{3-[(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-benzamide:Compound 2 was coupled with benzoic acid by procedure K. LC-MS showedthe product had the expected M+H⁺ of 560. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.35 ppm) 8.5 (d, 1H) 8.2 (d, 1H)8.1 (s, 1H) 8.0 (d, 2H) 7.6 (d, 2H), 7.4 (m, 5H), 7.1 (m, 2H), 6.7 (d,2H), 4.4 (s, 2H), 3.6 (t, 2H), 3.23 (d, 2H), 2.9 (s, 3H), 2.8 (t, 2H),1.8 (m, 2H).

Compound 57:N-{3-[(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-2-methyl-benzamide:Compound 2 was coupled with 2-methylbenzoic acid by procedure K. LC-MSshowed the product had the expected M+H⁺ of 574. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H) 8.2(s, 1H) 8.0 (d, 1H) 7.6 (m, 2H) 7.3 (m, 7H), 6.8 (d, 2H), 4.4 (s, 2H),3.7 (t, 2H), 3.3 (d, 2H), 3.2 (d, 2H) 184 (s, 3H), 2.3 (s, 3H), 1.8 (m,2H).

Compound 58:4-Chloro-N-{3-[(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-benzamide:Compound 2 was coupled with 4-chlorobenzoic acid following procedure K.LC-MS showed the product had the expected M+H⁺ of 594. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.23(d, 1H) 8.1 (d, 1H) 7.6 (d, 2H) 7.5 (d, 2H) 7.4 (m, 2H), 7.3 (d, 2H),7.1 (d, 2H), 7.0 (d, 2H), 6.7 (d, 2H), 4.5 (s, 2H) 3.6 (t, 2H), 3.1 (d,2H), δ 3.0 (s, 3H), 2.8 (t, 2H), δ 1.8 (m, 2H).

Compound 59:N-{3-[(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-4-methyl-benzamide:Compound 2 was coupled with 4-methylbenzoic acid following procedure K.LC-MS showed the product had the expected M+H⁺ of 574. ¹H NMR (Varian300 MHz, DMSO-d₆, shifts relative to the solvent peak at 2.49 ppm) δ 8.0(d, 2H) 7.65 (d, 2H) 7.50 (d, 2H) 7.2 (m, 3H) 7.0 (m, 3H), 6.7 (d, 2H),4.4 (s, 2H), 3.45 (t, 2H), 3.2 (d, 4H), 3.0 (s, 3H) 2.7 (t, 2H), 2.45(s, 3H), 1.8 (m, 2H).

Compound 60: Pyridine-2-carboxylic acid{3-[(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl)-amide:Compound 2 was coupled with pyridine-2-carboxylic acid followingprocedure K. LC-MS showed the product had the expected M+H⁺ of 561. ¹HNMR (Varian 300 MHz, DMSO-D6, shifts relative to the solvent peak at2.49 ppm) δ 8.7 (d, 1H) 8.6 (t, 1H) 8.3 (d, 1H) 8.0 (s, 1H) 7.9 (t, 1H),7.5 (m, 3H), 7.2 (t, 1H), 7.0 (m, 3H), 6.6 (d, 2H), 4.4 (s, 2H), δ 3.4(t, 2H), 3.2 (m, 4H), 3.0 (s, 3H), 2.7 (t, 2H), δ 1.7 (m, 2H).

Compound 61:3-Chloro-N-{3-[(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-benzamide:Compound 2 was coupled with 3-chlorobenzoic acid following procedure K.LC-MS showed the product had the expected M+H⁺ of 594. ¹H NMR (Varian300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.3(d, 1H) 7.82 (s, 1H) 7.7 (d, 1H) 7.55 (d, 2H) 7.2 (m, 2H), 7.3 (m, 2H),6.9 (m, 2H), 6.8 (d, 2H), 6.71 (d, 1H), 6.5 (d, 2H), δ 4.2 (s, 2H), 3.49(t, 2H), 3.2 (d, 2H), 3.5 (t, 2H), δ 2.6 (s, 3H), δ 1.4 (m, 2H).

Compound 62:3-Chloro-N-{3-[(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-benzamide:Compound 2 was coupled with 2-methyl nicotinic acid following procedureK. LC-MS showed the product had the expected M+H⁺ of 575. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4(d, 1H) 8.3 (d, 1H) 8.0 (d, 1H) 7.62 (m, 2H) 7.5 (t, 1H), 7.2 (d, 1H),7.0 (m, 4H), 6.7 (d, 2H), 4.5 (s, 2H), 3.6 (t, 2H), δ 3.3 (d, 4H), 3.0(s, 3H), 2.8 (t, 2H), 2.4 (s, 3H), δ 2.8 (t, 2H).

Compound 63:N-{3-[(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-2-methoxy-benzamide:Compound 2, was coupled with 2-methoxybenzoic acid following procedureK. LC-MS showed the product had the expected M+H⁺ of 590. ¹H NMR (Varian300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.2(d, 1H) 8.0 (s, 1H) 7.9 (s, 1H) 7.7 (t, 1H) 7.5 (m, 5H), 7.1 (d, 1H),6.9 (d, 2H), 6.8 (d, 2H), 4.5 (s, 2H), 3.8 (s, 3H), δ 3.7 (t, 2H), 3.5(t, 2H), 3.3 (t, 2H), 2.9 (t, 2H), δ 2.8 (s, 3H), δ 1.8 (m, 2H).

Compound 64:N-{3-[(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-C-phenyl-methanesulfonamide:Compound 2 was coupled with phenyl-methanesulfonyl chloride followingprocedure D. LC-MS showed the product had the expected M+H⁺ of 610. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.3 (d, 1H), 8.0 (d, 1H) 7.5 (m, 3H) 7.3 (d, 2H), 7.2 (m, 4H),6.7 (d, 4H), 4.4 (s, 2H), 4.2 (s, 2H), 3.6 (t, 2H), 3.2 (t, 2H), δ 2.9(s, 3H), 2.7 (t, 2H), 2.7 (t, 2H), δ 1.6 (m, 2H).

Compound 65:N-{3-[(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-propyl}-benzenesulfonamide:Compound 2 was coupled with benzenesulfonyl chloride following procedureD. LC-MS showed the product had the expected M+H⁺ of 596. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3(d, 1H), 8.0 (d, 1H) 7.5 (m, 3H) 7.3 (d, 2H), 7.2 (m, 4H), 6.7 (d, 4H),4.4 (s, 2H), 4.2 (s, 2H), 3.6 (t, 2H), 3.2 (t, 2H), δ 2.9 (s, 3H), 2.7(t, 2H), 2.7 (t, 2H), δ 1.6 (m, 2H).

Intermediate 8c: 3-(2-Chloro-pyrimidin-4-yl)-benzoic acid ethyl ester:2,4 dichloropyrimidine was coupled to 3-carboethoxyphenylboronic acidfollowing procedure A. LC-MS showed the product to be >95% pure and tohave the expected M+H⁺ of 195.

Compound 66:3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acidethyl ester: Intermediate 8c was coupled with tyramine followingprocedure F. LC-MS showed the product had the expected M+H⁺ of 364. ¹HNMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solvent peak at2.49 ppm) δ 9.15 (s, 1H) 8.72 (br s, 8.35 (m, 2H) 8.07 (d, 1H) 7.65 (m,1H) 7.18 (m, 1H) 7.05 (m, 2H) 6.68 (d, 2H) 4.35 (q, 2H) 3.5 (m, 2H) 2.78(m, 2H) 1.35 (t, 3H).

Intermediate 9:3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid:Compound 66 (2.4 g) was treated with 20 equivalents of sodium hydroxidein methanol. The mixture was heated at 50 C for 2 hours and the solventremoved by rotary evaporation. The residue was taken up in water andbrought to pH 7 by addition of 1N HCl. The solvent was again removed byrotary evaporation. LC-MS showed the product had the expected M+H⁺ of336. The crude product containing NaCl was used without purification inthe next step.

Compound 67:3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-N-pyrrolidin-3-ylmethyl-benzamide:Intermediate 9 (2.2 mmol) was coupled with3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5 mmol)using EDC (3 mmol) in DMF (20 mL). The DMF was removed by rotaryevaporation and the residue purified by flash chromatography on silicagel (ethyl acetate as eluent.) The resulting product was deprotectedfollowing procedure G. LC-MS showed the product had the expected M+H⁺ of418. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solventpeak at 2.49 ppm) δ 8.9 (s, 1H) 8.5-8.75 (m, 2H) 8.3 (m, 1H) 8.0 (d, 1H)7.65 (m, 1H) 7.3 (m, 1H) 7.05 (m, 2H) 6.68 (d, 2H) 3.6 (m, 2H) 3.4 (m,2H) 3.2-3.4 (m, 2H) 2.48 (m, 3H) 2.0 (m, 2H) 1.7 (m, 2H).

Compound 68:N-(3-Amino-propyl)-3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzamide:Intermediate 9 (1 mmol) was coupled with (3-Amino-propyl)-carbamic acidtert-butyl ester (3 mmol) using EDC (2 mmol) in DMF (10 mL). The DMF wasremoved by rotary evaporation and the residue purified by flashchromatography on silica gel (ethyl acetate as eluent.) The resultingproduct was deprotected following procedure G. LC-MS showed the producthad the expected M+H⁺ of 392. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.3 ppm) δ 8.68 (s, 1H) 8.35-8.5 (m, 3H)8.1 (d, 1H) 7.7 (m, 1H) 7.48 (d, 1H) 7.2 (d, 2H) 6.68 (d, 2H) 3.8 (m,2H) 3.55 (m, 2H) 3.05 (m, 2H) 2.9 (m, 4H) 2.0 (t, 2H).

Compound 69:3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-N-piperidin-2-ylmethyl-benzamide:Intermediate 9 (1 mmol) was coupled with2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3 mmol)using EDC (2 mmol) in DMF (10 mL). The DMF was removed by rotaryevaporation and the residue purified by flash chromatography on silicagel (ethyl acetate as eluent.) The resulting product was deprotectedfollowing procedure G. LC-MS showed the product had the expected M+H⁺ of432. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solventpeak at 2.49 ppm) δ 8.5-8.65 (m, 2H) 8.38 (m, 1H) 8.22 (m, 1H) 7.95 (m,1H) 7.55 (m, 1H) 7.28 (m, 1H) 7.20 (d, 1H) 7.05 (d, 2H) 6.68 (d, 2H) 3.5(m, 2H) 3.3 (m, 2H) 2.95 (m, 1H) 2.6-2.85 (m, 3H) 2.48 (m, 1H) 1.0-1.7(m, 6H).

Intermediate 10:[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-pyridin-2-ylmethyl-amine:Intermediate 1 was coupled with pyridin-2-yl-methylamine followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 311.

Intermediate 11:N-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-N-pyridin-2-ylmethyl-methanesulfonamide:Intermediate 10 was coupled with methanesulfonyl chloride followingprocedure D. LC-MS showed the product had the expected M+H⁺ of 389.

Compound 70:N-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-pyridin-2-ylmethyl-methanesulfonamide:Intermediate 11 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 490. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (d, 1H)8.3 (d, 1H) 7.9 (s, 2H) 7.6 (m, 1H) 7.4 (m, 2H) 7.3 (m, 2H) 7.2 (m, 1H)7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.5 (m, 1H) 4.5 (d, 4H) 3.7 (m, 2H)3.0 (s, 3H) 2.9 (m, 2H).

Intermediate 12:[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-pyridin-3-ylmethyl-amine:Intermediate 1 was coupled with pyridin-3-yl-methylamine followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 311.

Intermediate 13:N-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-N-pyridin-3-ylmethyl-methanesulfonamide:Intermediate 12 was coupled with methanesulfonyl chloride followingprocedure D. LC-MS showed the product had the expected M+H⁺ of 389.

Compound 71:N-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-pyridin-3-ylmethyl-methanesulfonamide:Intermediate 13 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 490. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.5 (d, 2H)8.4 (s, 1H) 8.3 (d, 1H) 7.9 (m, 4H) 7.4 (d, 2H) 7.3 (m, 1H) 7.1 (d, 2H)6.9 (d, 1H) 6.7 (d, 1H) 5.6 (m, 1H) 4.4 (d, 4H) 3.7 (m, 2H) 2.9 (m, 5H).

Intermediate 14:[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-pyridin-4-ylmethyl-amine:Intermediate 1 was coupled with pyridin-4-yl-methylamine followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 311.

Intermediate 15:N-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-N-pyridin-4-ylmethyl-methanesulfonamide:Intermediate 14 was coupled with methanesulfonyl chloride followingprocedure D. LC-MS showed the product had the expected M+H⁺ of 389.

Compound 72:N-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-pyridin-4-ylmethyl-methanesulfonamide:Intermediate 15 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 490. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 2H)8.2 (d, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.2 (d, 2H) 7.0 (d, 2H) 6.9 (d, 1H)6.7 (d, 2H) 4.4 (s, 2H) 4.3 (s, 2H) 3.6 (m, 2H) 2.9 (m, 5H).

Intermediate 16:[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-(2-pyridin-2-yl-ethyl)-amine:Intermediate 1 was coupled with 2-pyridin-2-yl-ethylamine followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 325.

Intermediate 17:N-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-N-(2-pyridin-2-yl-ethyl)-methanesulfonamide:Intermediate 16 was coupled with methanesulfonyl chloride followingprocedure D. LC-MS showed the product had the expected M+H⁺ of 403.

Compound 73:N-(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-(2-pyridin-2-yl-ethyl)-methanesulfonamide:Intermediate 17 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 504. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.5 (d, 1H)8.3 (d, 1H) 7.9 (m, 2H) 7.6 (m, 1H) 7.4 (m, 2H) 7.2 (m, 2H) 7.0 (d, 2H)6.9 (d, 1H) 6.7 (d, 2H) 5.4 (s, br, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.6 (m,2H) 3.0 (m, 2H) 2.8 (m, 2H) 2.8 (s, 3H).

Intermediate 18:[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-(2-pyridin-3-yl-ethyl)-amine:Intermediate 1 was coupled with 2-pyridin-3-yl-ethylamine followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 325.

Intermediate 19:N-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-N-(2-pyridin-3-yl-ethyl)-methanesulfonamide:Intermediate 18 was coupled with methanesulfonyl chloride followingprocedure D. LC-MS showed the product had the expected M+H⁺ of 403.

Compound 74:N-(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-(2-pyridin-3-yl-ethyl)-methanesulfonamide:Intermediate 19 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 504. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 1H)8.3 (s, 2H) 8.0 (s, 1H) 7.9 (d, 1H) 7.5 (m, 3H) 7.2 (m, 1H) 7.0 (d, 2H)6.9 (d, 1H) 6.7 (d, 2H) 5.5 (m, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.4 (m, 2H)2.8 (m, 7H).

Intermediate 20:[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-(2-pyridin-4-yl-ethyl)-amine:Intermediate 1 was coupled with 2-pyridin-4-yl-ethylamine followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 325.

Intermediate 21:N-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-N-(2-pyridin-4-yl-ethyl)-methanesulfonamide:Intermediate 20 was coupled with methanesulfonyl chloride followingprocedure D. LC-MS showed the product had the expected M+H⁺ of 403.

Compound 75:N-(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-(2-pyridin-4-yl-ethyl)-methanesulfonamide:Intermediate 21 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 504. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 2H)8.3 (d, 1H) 8.0 (s, 1H) 7.9 (m, 1H) 7.5 (m, 2H) 7.0 (m, 4H) 6.9 (d, 1H)6.7 (d, 2H) 5.5 (m, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.5 (, 2H) 2.8 (m, 7H).

Intermediate 22: [3-(2-chloro-pyrimidin-4-yl)-benzyl]-ethyl-amine:Intermediate 1 was coupled with ethylamine following procedure B. LC-MSshowed the product had the expected M+H⁺ of 248.

Intermediate 23:[3-(2-chloro-pyrimidin-4-yl)-benzyl]-ethyl-pyridin-3-ylmethyl-amine:Intermediate 22 was coupled with pyridine-3-carboxaldehyde followingprocedure E. LC-MS showed the product had the expected M+H⁺ of 339.

Compound 76:4-[2-(4-{3-[(Ethyl-pyridin-3-ylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 23 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 440. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.63 (s, 1H)8.49 (m, 1H) 8.26 (m, 1H) 8.15 (s, 1H) 8.05 (s, 1H) 7.45 (m, 2H) 7.25(m, 1H) 7.05 (m, 3H) 6.99 (d, 1H) 6.75 (m, 4H) 3.4-3.8 (m, 4H) 2.88 (t,2H) 2.75 (t, 2H) 2.55 (m, 2H) 1.05 (t, 3H).

Intermediate 24:4-{2-[4-(3-Amino-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol: Compound 52was reduced by procedure I. LC-MS showed the product had the expectedM+H⁺ of 307. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to thesolvent peak at 2.49 ppm) δ 9.2 (d, 1H) 8.8 (t, 1H) 8.3 (d, 1H) 7.9 (d,1H) 7.4-6.9 (m 4H), 6.7 (d, 1H), 3.4 (t, 2H), 2.8 (t 2H).

Compound 77:3-Amino-N-(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-propionamide:Intermediate 24 was coupled to 3-tert-butoxycarbonylamino-propionic acidby procedure K. The resulting product was deprotected by procedure G.LC-MS showed the product had the expected M+H⁺ of 377. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.6(d, 1H) 8.4 (d, 1H) 8.1 (s, 1H) 7.8 (d, 1H) 7.5 (t 3H), 7.2 (d, 1H), 7.1(d, 2H), 6.7 (d 2H), 3.6 (d, 2H), 3.1 (d, 2H), 2.8 (d, 2H), 2.5 (d, 2H).

Compound 78:N-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-3-pyridin-3-yl-propionamide:Intermediate 24 was coupled to 3-Pyridin-3-yl-propionic acid followingprocedure K. LC-MS showed the product had the expected M+H⁺ of 440. ¹HNMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solvent peak at2.49 ppm) δ 9.1 (s, 1H), 8.5 (d, 1H) 8.3 (d, 1H) 7.7 (m, 3H), 7.4 (t,1H), 7.3 (t, 1H), 7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 2H), 6.7 (d, 2H), δ3.5 (t, 2H), 2.9 (t, 2H), 2.8 (t, 2H), δ 2.7 (t, 2H).

Compound 79:N-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-C-phenyl-methanesulfonamide:Intermediate 24 was coupled with phenyl-methylsulfonyl chloridefollowing procedure D. LC-MS showed the product had the expected M+H⁺ of461. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solventpeak at 2.49 ppm) δ 8.4 (d, 1H), 8.0 (d, 1H) 7.8 (d, 1H) 7.5 (t, 2H),7.3 (m, 4H), 7.1 (d, 2H), 7.0 (d, 2H), 6.9 (d, 2H), 4.5 (s, 2H), 3.5 (t,2H), δ 2.8 (t, 2H).

Intermediate 25:4-[2-(4-{3-[(Pyridin-3-ylmethyl)-amino]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 24 was coupled with pyridine 3-carboxaldehyde followingprocedure E. LC-MS showed the product had the expected M+H⁺ of 398. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.6 (s, 1H), 8.4 (d, 1H) 8.2 (d, 1H) 7.8 (d, 1H), 7.4-7.3 (m,3H), 7.2 (t, 1H), 7.1 (d, 2H), 6.9 (d, 2H), 6.8 (d, 1H), 6.7 (d, 1H), δ4.4 (s, 2H), δ 3.6 (t, 2H), 2.8 (t, 2H).

Compound 80:4-(2-{4-[3-(Ethyl-pyridin-3-ylmethyl-amino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 25 was coupled with acetaldehyde following procedure E.LC-MS showed the product had the expected M+H⁺ of 426. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4(s, 1H) 8.39 (d, 1H) 8.2 (d, 1H) 7.6 (d, 1H) 7.5 (s, 1H), 7.3 (m, 3H),7.0 (d, 1H), 6.9 (d 1H), 6.8 (d, 2H), 6.5 (d, 2H), 4.6 (s, 2H), 3.6 (m,4H), 2.8 (t, 2H), 1.2 (d, 3H).

Intermediate 26: 2-Chloro-4-(3-dimethoxymethyl-phenyl)-pyrimidine:Intermediate 1 (3.69 g) was refluxed for two hours intrimethylorthoformate containing 10 mL of 4N HCl/dioxane. The solventwas removed by rotary evaporation to give product, which showed theexpected M+H⁺ of 265 by LC-MS.

Intermediate 27:4-{2-[4-(3-Dimethoxymethyl-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 26 was coupled with tyramine following procedure F. Theproduct was purified by flash chromatography using 99:1 CH₂Cl₂:MeOH aseluent. Yield: 35%. LC-MS showed the product had the expected M+H⁺ of366.

Intermediate 28:3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde:Intermediate 27 (2.2 g) was treated with 30 mL of 3N HCl in 60 mL ofCH₃CN at room temperature overnight. The solvent was removed by rotaryevaporation and the residue partitioned between ethyl acetate/sat.NaHCO₃. Yield: 1.9 g, 99%. LC-MS showed the product had the expectedM+H⁺ of 320.

Compound 81:4-(2-{4-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 28 was coupled with N-methyl piperazine following procedureF. LC-MS showed the product had the expected M+H⁺ of 404. ¹H NMR (Varian300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.3(d, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.1 (d, 2H) 7.0 (d, 1H) 6.7 (d, 2H) 5.2(m, 1H) 3.7 (m, 2H) 3.6 (s, 2H) 2.9 (m, 2H) 2.7 (s, 8H) 2.4 (s, 3H).

Compound 82:4-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-3-(S)methyl-piperazine-1-carboxylic acid tert-butyl ester: Intermediate 28was coupled with 3-(S) methyl-piperazine-1-carboxylic acid tert-butylester following procedure B. LC-MS showed the product had the expectedM+H⁺ of 504. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to thesolvent peak at 7.24 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.5 (m,2H) 7.1 (d, 2H) 7.0 (d, 1H) 6.7 (d, 2H) 5.5 (s, br, 1H) 4.1 (m, 1H) 3.7(m, 6H) 3.1-3.5 (m, 2H) 2.9 (m, 2H) 2.6-2.8 (m, 2H) 1.5 (s, 9H) 1.3 (m,3H).

Compound 83:4-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-3-(R)methyl-piperazine-1-carboxylic acid tert-butyl ester: Intermediate 28was coupled with 3-(R) methyl-piperazine-1-carboxylic acid tert-butylester following procedure B. LC-MS showed the product had the expectedM+H⁺ of 504. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to thesolvent peak at 7.24 ppm) δ8.3 (d, 1H) 8.1 (s, 1H) 7.9 (d, 1H) 7.5 (m,2H) 7.1 (d, 2H) 7.0 (d, 1H) 6.7 (d, 2H) 5.5 (s, br, 1H) 4.1 (m, 1H) 3.7(m, 6H) 3.1-3.5 (m, 2H) 2.9 (m, 2H) 2.6-2.8 (m, 2H) 1.5 (s, 9H) 1.3 (m,3H).

Compound 84:4-(2-{4-[3-(2(S)-Methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Compound 83 was deprotected following procedure G2. LC-MS showed theproduct had the expected M+H⁺ of 404. ¹H NMR (Varian 300 MHz, DMSO-d₆,shifts relative to the solvent peak at 2.49 ppm) δ 9.2 (s, 1H) 8.9 (s,br, 1H) 8.3 (d, 1H) 8.0 (d, 2H) 7.5 (s, 2H) 7.3 (m, 1H) 7.1 (d, 1H) 7.0(d, 2H) 6.7 (d, 2H) 4.1 (d, 1H) 3.5 (d, 2H) 3.3 (m, 3H) 3.1 (m, 2H) 2.7(m, 4H) 2.3 (m, 1H) 1.2 (d, 3H).

Compound 85:4-(2-{4-[3-(2(R)-Methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Compound 83 was deprotected following procedure G2. LC-MS showed theproduct had the expected M+H⁺ of 404. ¹H NMR (Varian 300 MHz, DMSO-d₆,shifts relative to the solvent peak at 2.49 ppm) δ 9.2 (s, 1H) 8.9 (s,br, 1H) 8.3 (d, 1H) 8.0 (d, 2H) 7.5 (s, 2H) 7.3 (m, 1H) 7.1 (d, 1H) 7.0(d, 2H) 6.7 (d, 2H) 4.1 (d, 1H) 3.5 (d, 2H) 3.3 (m, 3H) 3.1 (m, 2H) 2.7(m, 4H) 2.3 (m, 1H) 1.2 (d, 3H).

Intermediate 29:4-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-piperidine-1-carboxylic acidtert-butyl ester: Intermediate 1 was coupled with4-Amino-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 403.

Intermediate 30:4-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 29 was coupled with methanesulfonylchloride following procedure D. LC-MS showed the product had theexpected M+H⁺ of 481. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.3 ppm) δ 8.4 (s, 1H) 8.39 (d, 1H) 8.2 (d, 1H) 7.6(d, 1H) 7.5 (s, 1H), 7.3 (m, 3H), 7.0 (d, 1H), 6.9 (d 1H), 6.8 (d, 2H),6.5 (d, 2H), 4.6 (s, 2H), 3.6 (m, 4H), 2.8 (t, 2H), 1.2 (d, 3H).

Compound 86:N-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 30 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G. LC-MS showedthe product had the expected M+H⁺ of 482. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (d, 1H), δ 8.2 (s,1H) 8.0 (d, 1H) 7.6 (d, 1H), 7.5 (t, 1H), 7.1 (m, 3H), 6.8 (d, 2H), 4.5(s, 2H), 3.6 (t, 2H), δ 3.0 (s, 3H), 2.9 (m, 5H), δ 2.8 (t, 2H), 2.0 (m,4H).

Compound 87:N-(3-{2-[2-(3-Fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 30 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 484. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.4 (s, 1H), 8.3 (d, 1H) 8.1 (d, 1H) 7.7 (d, 1H), 7.5 (m, 1H),7.3 (m, 2H), 7.1 (m, 2H), 6.9 (t, 1H), 4.6 (s, 2H), δ 3.4 (t, 2H), 3.09(s, 3H), δ 3.05 (m, 5H), 3.04 (t, 2H), 2.08 (m, 4H).

Compound 88:N-[3-(2-Phenethylamino-pyrimidin-4-yl)-benzyl]-N-piperidin-4-yl-methanesulfonamide:Intermediate 30 was coupled with phenethylamine following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 466. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H),8.1 (d, 2H) 7.7 (d, 2H) 7.5 (t, 2H), 7.2 (m, 3H), 7.1 (d, 1H), 4.6 (s,2H), δ 3.4 (t, 2H), 3.09 (s, 3H), δ 3.05 (m, 7H), 2.0 (m, 4H).

Compound 89:N-(3-{2-[2-(3-Chloro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 30 was coupled with 2-(3-chloro-phenyl)-ethylaminefollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 500. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.3 (d, 1H), 8.1 (d, 1H) 7.7 (d, 1H) 7.5 (t, 1H), 7.3 (m, 2H),7.25 (m, 3H), 7.20 (d, 1H), δ 4.6 (s, 2H), δ 3.3 (t, 2H), 3.09 (s, 3H),δ 3.04 (m, 7H), 2.0 (m, 4H).

Compound 90:N-(3-{2-[2-(4-Hydroxy-3-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 30 was coupled with 4-(2-amino-ethyl)-2-methoxy-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 512. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.3 (d, 1H), 8.0 (d, 2H) 7.6 (m, 2H), 7.5 (t, 1H), 7.2 (d, 1H),6.8 (d, 1H), δ 6.7 (s, 1H), 4.5 (d, 2H), δ 3.8 (s, 3H), 3.3 (t, 2H), δ3.0 (s, 3H), 2.9 (m, 5H), δ 2.8 (t, 2H), δ 2.0 (m, 4H).

Intermediate 31:3-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-piperidine-1-carboxylic acidtert-butyl ester: Intermediate 1 was coupled with3-Amino-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 403.

Intermediate 32:3-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 30 was coupled with methanesulfonylchloride following procedure D. LC-MS showed the product had theexpected M+H⁺ of 481.

Compound 91:N-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 31 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G. LC-MS showedthe product had the expected M+H⁺ of 482. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.32 (d, 1H), 8.31 (s,1H) 7.7 (d, 2H), 7.6 (t, 1H), 7.3 (d, 2H), 7.1 (d, 1H), δ 6.7 (d, 2H),4.6 (d, 2H), δ 3.3 (t, 2H), 3.1 (s, 3H), δ 2.9 (m, 5H), 2.7 (t, 2H), δ2.1-1.7 (m, 4H).

Compound 92:N-(3-{2-[2-(4-Hydroxy-3-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-3-yl-methanesulfonamide:Intermediate 31 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 512. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.2 (d, 1H), 8.1 (d, 2H) 7.6 (d, 1H) 7.5 (t, 1H), 7.3 (d, 1H),6.8 (d, 1H), 6.7 (s, 1H), δ 4.6 (s, 2H), 3.8 (s, 3H), δ 3.2 (t, 2H), 3.1(s, 3H), δ 2.9-2.7 (m, 7H), δ 2.1-1.7 (m, 4H).

Intermediate 33:4-{[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 417.

Intermediate 34:4-({[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 33 was coupled with methane sulfonylchloride following procedure D. LC-MS showed the product had theexpected M+H⁺ of 495.

Compound 93:N-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-ylmethyl-methanesulfonamide:Intermediate 34 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G. LC-MS showedthe product had the expected M+H⁺ of 496. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 2H), 8.1 (d,1H) 7.6 (d, 1H) 7.5 (t, 1H), 7.3 (d, 1H), 7.1 (d, 2H), 6.7 (d, 2H), δ4.5 (s, 2H), 3.3-3.2 (m, 6H), δ 3.0 (s, 3H), 2.9 (t, 2H), δ 2.7 (t, 2H),δ 1.6 (m, 1H), δ 1.2 (m, 4H).

Intermediate 35:3-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 389.

Intermediate 36:3-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester: Intermediate 35 was coupled with methanesulfonylchloride following procedure D. LC-MS showed the product had theexpected M+H⁺ of 467.

Compound 94:3-[(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-pyrrolidine-1-carboxylicacid tert-butyl ester: Intermediate 36 was coupled with tyraminefollowing procedure F. The resulting product was deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 468. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.2 (d, 2H), 8.0 (d, 1H) 7.6 (d, 1H) 7.5 (t, 1H), 7.2 (d, 1H),7.1 (d, 2H), 6.7 (d, 2H), δ 4.6 (s, 2H), 3.5-3.4 (m, 6H), δ 3.2-3.1 (m,1H), 3.0 (s, 3H), δ 2.9 (t, 2H), δ 2.2-2.0 (m, 2H).

Intermediate 37: [3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-carbamicacid tert-butyl ester: Intermediate 22 (2.46 g) was treated with di-tertbutyl dicarbonate (2.62 g) and diisopropylethylamine (2.6 mL) inmethylene chloride (100 mL). The mixture was stirred at room temperaturefor 1 hour, washed with water (3×100 mL), dried over MgSO₄, and thesolvent removed to give 2.15 g of product. LC-MS showed the product hadthe expected M+H⁺ of 348.

Compound 95:2-Chloro-4-{2-[4-(3-ethylaminomethyl-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 37 was coupled with intermediate 71 following procedure Fand the resulting product deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 383. ¹H NMR (Varian 300 MHz,DMSO-d₆, shifts relative to the solvent peak at 2.49 ppm) δ 9.5 (s, 2H)8.5 (m, 3H) 8.2 (d, 1H) 7.8 (d, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.3 (s, 1H)7.0 (d, 1H) 6.9 (d, 1H) 4.2 (s, 2H) 4.0 (m, 2H) 3.0 (m, 2H) 2.8 (m, 2H)1.3 (m, 3H).

Compound 96:[4-(3-Ethylaminomethyl-phenyl)-pyrimidin-2-yl]-[2-(3-fluoro-phenyl)-ethyl]-amine:Intermediate 37 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F and the resulting product deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 351. ¹HNMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solvent peak at2.49 ppm) δ 9.5 (s, 2H) 8.5 (m, 2H) 8.2 (d, 1H) 7.8 (d, 1H) 7.6 (m, 1H)7.5 (ms, 1H) 7.3 (m, 1H) 7.1 (m, 2H) 7.0 (m, 1H) 4.2 (s, 2H) 3.8 (m, 2H)2.9 (m, 4H) 1.2 (m, 3H).

Compound 97:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-ethyl-methanesulfonamide:Compound 94 was coupled with methanesulfonyl chloride followingprocedure D. LC-MS showed the product had the expected M+H⁺ of 461. ¹HNMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solvent peak at2.49 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (s, 1H) 7.5 (d, 2H) 7.3 (m, 1H)7.2 (s, 1H) 7.1 (d, 1H) 7.0 (d, 1H) 6.9 (d, 1H) 4.4 (s, 2H) 3.5 (m, 2H)3.2 (m, 2H) 3.0 (s, 3H) 2.8 (m, 2H) 1.0 (m, 3H).

Compound 98:2-Chloro-4-[2-(4-{3-[(ethyl-isopropyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Compound 94 was coupled with acetone following procedure E. LC-MS showedthe product had the expected M+H⁺ of 425. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H) 8.2 (s,1H) 8.1 (m, 1H) 7.5 (m, 2H) 7.2 (d, 1H) 7.1 (d, 1H) 7.0 (m, 1H) 6.8 (d,1H) 4.1 (s, 2H) 3.6 (m, 2H) 3.4 (m, 1H) 2.9 (m, 4H) 1.3 (d, 6H) 1.2 (m,3H).

Compound 99:2-Chloro-4-{2-[4-(3-{[ethyl-(3-methyl-butyl)-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Compound 94 was coupled with 3-Methyl-butyraldehyde following procedureE. LC-MS showed the product had the expected M+H⁺ of 453. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3(d, 1H) 8.2 (s, 1H) 8.1 (m, 1H) 7.5 (m, 2H) 7.2 (d, 1H) 7.1 (d, 1H) 7.0(m, 1H) 6.8 (d, 1H) 4.0 (s, 2H) 3.6 (m, 2H) 2.8 (m, 6H) 1.5 (m, 3H) 1.2(m, 3H) 0.9 (d, 6H).

Compound 100:2-Chloro-4-{2-(4-{3-[(ethyl-isobutyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl}-phenol:Compound 94 was coupled with 2-Methyl-propionaldehyde followingprocedure E. LC-MS showed the product had the expected M+H⁺ of 439. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.3 (d, 1H) 8.2 (s, 1H) 8.0 (m, 1H) 7.5 (m, 2H) 7.2 (d, 1H) 7.1(d, 1H) 7.0 (m, 1H) 6.8 (d, 1H) 3.8 (s, 2H) 3.6 (m, 2H) 2.8 (m, 2H) 2.7(m, 2H) 2.4 (d, 2H) 1.9 (m, 1H) 1.1 (m, 3H) 0.9 (m, 6H).

Compound 101:2-Chloro-4-{2-[4-(3-diethylaminomethyl-phenyl)-pyrimidin-2-ylamino]ethyl}-phenol:Compound 94 was coupled with acetaldehyde following procedure E. LC-MSshowed the product had the expected M+H⁺ of 425. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H) 8.2(s, 1H) 8.0 (m, 1H) 7.5 (m, 2H) 7.2 (d, 1H) 7.1 (d, 1H) 7.0 (m, 1H) 6.8(d, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 2.8 (m, 4H) 2.7 (m, 2H) 1.6 (m, 2H) 1.2(m, 3H) 0.9 (m, 3H).

Intermediate 38: 1-[3-(2-Chloro-pyrimidin-4-yl)-phenyl]-ethanone: 2,4dichloropyrimidine was coupled with 3-acetylphenylboronic acid followingprocedure A. LC-MS showed the product had the expected M+H⁺ of 234.

Intermediate 39:1-(3-{2-[2-(4-Methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-ethanone:Intermediate 38 was coupled with 2-(4-Methoxy-phenyl)-ethylaminefollowing procedure F. LC-MS showed the product had the expected M+H⁺ of348.

Intermediate 40:N1-[1-(3-{2-[2-(4-Methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-ethyl]-propane-1,3-diamine:Intermediate 39 was coupled with (3-Amino-propyl)-carbamic acidtert-butyl ester following procedure C. LC-MS showed the product had theexpected M+H⁺ of 506.

Compound 102: Intermediate 40 was deprotected following procedure G.LC-MS showed the product had the expected M+H⁺ of 406. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4(m, 3H) 7.6-7.9 (m, 2H) 7.48 (d, 1H) 7.2 (m, 3H) 6.8 (d, 2H) 4.55 (q,1H) 3.85 (m, 1H) 3.68 (s, 3H) 3.15 (m, 1H) 2.95 (m, 6H) 2.08 (m, 2H)1.78 (d, 3H).

Compound 103: Intermediate 40 was coupled with methanesulfonyl chloridefollowing procedure D. The resulting product was deprotected followingprocedure G. LC-MS showed the product had the expected M+H⁺ of 484. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.3 (br s, 1H) 8.2 (d, 1H) 7.78 (d, 1H) 7.6 (m, 1H) 7.38 (m, 1H)7.2 (d, 2H) 6.8 (d, 2H) 5.3 (q, 1H) 3.8 (br s, 2H) 3.75 (s, 3H) 3.2-3.4(m, 2H) 3.05-3.1 (m, 2H) 2.95 (s, 3H) 2.78 (m, 2H) 1.77 (d, 3H) 1.6 (m,2H).

Compound 104: Compound 103 (0.1 g) was treated with BBr₃ (0.1 mL) inCH₂Cl₂ (10 mL) at 0 C for ½ hour. The solvent was evaporated and thecrude mixture subjected to HPLC purification. LC-MS showed the producthad the expected M+H⁺ of 470. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.3 ppm) δ 8.5 (br s, 1H) 8.2-8.35 (m,3H) 8.05 (d, 1H) 7.65 (d, 1H) 7.52 (m, 1H) 7.1 (d, 2H) 6.7 (d, 2H) 5.25(q, 1H) 3.63 (t, 2H) 3.2-3.4 (m, 2H) 2.96 (s, 3H) 2.85 (m, 2H) 2.7 (m,2H) 1.72 (d, 3H) 1.6 (m, 2H).

Intermediate 41: (3-Benzoylamino-propyl)-carbamic acid tert-butyl ester:(3-Amino-propyl)-carbamic acid tert-butyl ester (1.6 g) was treated withbenzoyl chloride (1.1 eq.) and triethylamine (1.5 eq) in methylenechloride (50 mL). The reaction mixture was washed with 1 N HCl, sat,NaHCO3, and sat NaCl and the solvent removed to give product. LC-MSshowed the product had the expected M+H⁺ of 279.

Intermediate 42: N-(3-Amino-propyl)-benzamide: Intermediate 41 wasdeprotected by procedure G. LC-MS showed the product had the expectedM+H⁺ of 179.

Intermediate 43:N-{3-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-propyl}-benzamide:Intermediate 42 was coupled with intermediate 1 following procedure B.LC-MS showed the product had the expected M+H⁺ of 381.

Intermediate 44:N-(3-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-propyl)-benzamide:Intermediate 43 was coupled with acetaldehyde following procedure E.LC-MS showed the product had the expected M+H⁺ of 409.

Compound 105:N-{3-[Ethyl-(3-{2-{2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-amino}-propyl}-benzamide:Intermediate 44 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 510.

Intermediate 45: 2-Chloro-4-(3-isopropoxy-phenyl)-pyrimidine: 2,4dichlorpyrimidine was coupled with 3-isopropoxyphenylboronic acidfollowing procedure A. LC-MS showed the product had the expected M+H⁺ of249.

Compound 106:4-{2-[4-(3-Isopropoxy-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 45 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 350. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (m, 1H)7.6 (m, 2H) 7.35 (m, 1H) 7.0 (m, 4H) 6.68 (m, 2H) 5.5 (m, 1H) 4.62 (m,1H) 3.71 (m, 2H) 2.85 (m, 2H) 1.32 (d, 6H).

Compound 107:4-{2-[4-(3-Isopropoxy-phenyl)-pyrimidin-2-ylamino]-ethyl}-2-methoxy-phenol:Intermediate 45 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenolfollowing procedure F. LC-MS showed the product had the expected M+H⁺ of380. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.3 (m, 1H) 7.6 (m, 2H) 7.36 (m, 1H) 6.9 (m, 2H) 6.83 (m,1H) 6.72 (m, 2H) 5.5 (m, 1H) 4.62 (m, 1H) 3.75 (s, 3H) 3.7 (m, 2H) 2.88(m, 2H) 1.32 (d, 6H).

Intermediate 46: 4-(3-Butoxy-phenyl)-2-chloro-pyrimidine: 2,4dichloropyrimidine was coupled with 3-butoxyphenylboronic acid followingprocedure A. LC-MS showed the product had the expected M+H⁺ of 263.

Compound 108:4-{2-[4-(3-Butoxy-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 46 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 364. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (m, 1H)7.6 (m, 2H) 7.35 (m, 1H) 7.0 (m, 4H) 6.7 (d, 2H) 5.49 (br s, 1H) 4.0 (t,2H) 3.7 (d, 2H) 2.85 (t, 2H) 1.78 (d, 2H) 1.5 (d, 2H) (t, 3H).

Compound 109:4-{2-[4-(3-Butoxy-phenyl)-pyrimidin-2-ylamino]-ethyl}-2-methoxy-phenol:Intermediate 46 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenolfollowing procedure F. LC-MS showed the product had the expected M+H⁺ of394. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.3 (m, 1H) 7.6 (m, 2H) 7.35 (m, 1H) 7.0 (m, 2H) 6.85 (m,1H) 672 (m, 2H) 5.51 (br s, 1H) 4.0 (t, 2H) 3.75 (s, 3H) 3.7 (m, 2H)2.89 (t, 2H) 1.78 (d, 2H) 1.5 (d, 2H) (t, 3H).

Intermediate 47: 4-(4-ethoxy-phenyl)-2-chloro-pyrimidine: 2,4dichloropyrimidine was coupled with 3-ethoxyphenylboronic acid followingprocedure A. LC-MS showed the product had the expected M+H⁺ of 235.

Compound 110:4-{2-[4-(4-ethoxy-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 47 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 336. ¹H NMR (Varian 300 MHz,DMSO-d₆, shifts relative to the solvent peak at 2.49 ppm) δ 8.2 (d, 1H),8.0 (d, 2H) 7.0 (m, 4H) 6.6 (d, 3H), δ 4.0 (q, 2H), 3.4 (t, 2H), δ 2.7(t, 2H), 1.3 (t, 3H).

Compound 111:4-{2-[4-(4-ethoxy-phenyl)-pyrimidin-2-ylamino]-ethyl}-2-methoxy-phenol:Intermediate 47 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenolfollowing procedure F. LC-MS showed the product had the expected M+H⁺ of366. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solventpeak at 2.49 ppm) δ 8.0 (d, 1H), 7.1-7.0 (m, 4H) 6.8 (s, 1H), δ 6.7-6.6(m, 3H), δ 4.0 (q, 2H), δ 3.7 (s, 3H), 3.5 (t, 2H), δ 2.7 (t, 2H), 1.3(t, 3H).

Intermediate 48: [4-(2-Chloro-pyrimidin-4-yl)-phenyl]-carbamic acidbenzyl ester: 2,4 dichloropyrimidine was coupled with4-carbobenzyloxyphenylboronic acid following procedure A. LC-MS showedthe product had the expected M+H⁺ of 340.

Compound 112:(4-{2-[2-(4-Hydroxy-3-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-carbamicacid benzyl ester: Intermediate 48 was coupled with4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showedthe product had the expected M+H⁺ of 471. ¹H NMR (Varian 300 MHz, CDCl₃,shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (m, 1H) 8.0 (d,2H) 7.5 (d, 2H) 7.4 (m, 4H) 7.05 (s, 1H) 6.9 (d, 1H) 6.83 (m, 1H) 6.7(m, 2H) 5.55 (br s, 1H) 5.21 (s, 2H) 3.81 (s, 3H) 3.7 (t, 2H) 2.9 (t,2H).

Intermediate 49: 2-Chloro-4-(4-isobutyl-phenyl)-pyrimidine: 2,4dichloropyrimidine was coupled with 4-isobutylphenylboronic acidfollowing procedure A. LC-MS showed the product had the expected M+H⁺ of247.

Compound 113:4-{2-[4-(4-Isobutyl-phenyl)-pyrimidin-2-ylamino]-ethyl}-2-methoxy-phenol:Intermediate 49 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenolfollowing procedure F. LC-MS showed the product had the expected M+H⁺ of378. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.3 (m, 1H) 7.99 (d, 2H) 7.25 (d, 2H) 6.95 (d, 1H) 6.85(m, 1H) 6.74 (m, 2H) 5.5 (br s, 1H) 3.8 (s, 3H) 3.75 (m, 2H) 2.87 (t,2H) 2.52 (t, 2H) 1.88 (m, 1H) 0.9 (d, 6H).

Intermediate 50: 2-Chloro-4-(4-propoxy-phenyl)-pyrimidine: 2,4dichloropyrimidine was coupled with 4-propoxyphenylboronic acidfollowing procedure A. LC-MS showed the product had the expected M+H⁺ of249.

Compound 114:2-Methoxy-4-{2-[4-(4-propoxy-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 50 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenolfollowing procedure F. LC-MS showed the product had the expected M+H⁺ of380. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to the solventpeak at 2.49 ppm) δ 8.0 (d, 1H), 7.1-7.0 (m, 4H) 6.8 (s, 1H), δ 6.7-6.6(m, 3H), δ 4.0 (t, 2H), δ 3.7 (s, 3H), 3.5 (t, 2H), δ 2.7 (t, 2H), δ1.8-1.7 (m, 2H), 0.9 (t, 3H).

Intermediate 51:3-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-piperidine-1-carboxylic acidtert-butyl ester: Intermediate 1 was coupled with3-Amino-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 403.

Intermediate 52:3-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 51 was coupled with methanesulfonylchloride following procedure D. LC-MS showed the product had theexpected M+H⁺ of 481.

Compound 115:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-3-yl-methanesulfonamide:Intermediate 52 was coupled with intermediate 71 following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 516. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), δ8.1 (d, 1H), δ 7.6 (d, 1H), 7.5 (t, 1H), 7.3 (d, 1H) 7.2 (d, 1H), δ 7.1(d, 1H), δ 7.0 (d, 1H), 6.8 (d, 1H), δ 4.6 (s, 2H), δ 3.7 (t, 2H), δ 3.2(t, 2H), 3.1 (s, 3H), δ 2.9-2.8 (m, 4H), δ 2.8-2.7 (m, 1H), δ 2.1-1.7(m, 4H).

Intermediate 53:3-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3-Amino-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 389.

Intermediate 54:3-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester: Intermediate 53 was coupled with methanesulfonylchloride following procedure D. LC-MS showed the product had theexpected M+H⁺ of 467.

Compound 116:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-pyrrolidin-3-yl-methanesulfonamide:Intermediate 54 was coupled with intermediate 71 following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 502. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), δ8.2 (s, 1H), 8.0 (d, 1H) 7.6 (d, 1H) 7.5 (t, 1H), 7.2 (d, 1H), 7.1 (d,1H), δ 7.0 (d, 1H), 6.8, d, 1H), δ 4.6 (s, 2H), m, 6Hδ 3.2-3.1 (m, 1H),3.1 (s, 3H), δ 2.9 (t, 2H), δ 2.3-2.1 (m, 2H).

Intermediate 55:4-{[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 417.

Intermediate 56:4-({[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 55 was coupled with methanesulfonylchloride following procedure D. LC-MS showed the product had theexpected M+H⁺ of 495.

Compound 117:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-ylmethyl-methanesulfonamide:Intermediate 56 was coupled with intermediate 71 following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 530. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H),8.1 (d, 1H) 7.6 (d, 1H) 7.5 (t, 1H), 7.3 (s, 1H), 7.2 (d, 1H), 7.1 (d,1H), δ 7.0 (d, 1H), δ 6.8 (d, 1H), δ 4.5 (s, 2H), 3.3-3.2 (m, 6H), δ 3.0(s, 3H), δ 2.9 (t, 2H), δ 2.7 (t, 2H), δ 1.7-1.6 (m, 1H), δ 1.3-1.2 (m,4H).

Intermediate 57:2-{2-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with2-(2-Amino-ethyl)-piperidine-1-carboxylic acid tert-butyl esterfollowing procedure B. LC-MS showed the product had the expected M+H⁺ of431.

Intermediate 58:2-(2-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-ethyl)-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 57 was coupled with methanesulfonylchloride following procedure D. LC-MS showed the product had theexpected M+H⁺ of 509.

Compound 118:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-(2-piperidin-2-yl-ethyl)-methanesulfonamide:Intermediate 58 was coupled with intermediate 71 following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 544. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H),8.1 (d, 1H) 7.7 (d, 1H) 7.6 (t, 1H), 7.3 (d, 1H), 7.2 (d, 1H), 7.1 (d,1H), δ 7.0 (d, 1H), δ 6.8 (d, 1H), δ 4.5 (s, 2H), 3.5-3.4 (m, 5H), δ 3.2(t, 2H), δ 3.0 (s, 3H), δ 2.9 (t, 2H), δ 1.8-1.7 (m, 4H), δ 1.6-1.5 (m,2H), δ 1.4-1.2 (m, 2H).

Compound 119:N1-Ethyl-N1-(3-{2-[2-(4-methoxy-3-methyl-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-propane-1,3-diamine:Intermediate 3 was coupled with 2-(4-Methoxy-3-methyl-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected byprocedure G. LC-MS showed the product had the expected M+H⁺ of 434. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.4 (m, 2H) 8.0 (s, 1H) 7.6-7.8 (m, 2H) 7.47 (d, 1H) 6.82 (d, 1H)6.67 (m, 2H) 4.5 (s, 2H) 3.81 (s, 3H) 3.4 (m, 4H) 3.28 (m, 4H) 3.03 (t,2H) 2.68 (t, 2H) 2.16 (m, 2H) 1.4 (t, 3H).

Intermediate 59:3-{[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 403.

Intermediate 60:3-({Acetyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-amino}-methyl)-pyrrolidine-1-carboxylicacid tert-butyl ester: Intermediate 59 was coupled with acetyl chloridefollowing procedure D. LC-MS showed the product had the expected M+H⁺ of445.

Compound 120:N-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-pyrrolidin-3-ylmethyl-acetamide:Intermediate 60 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G. LC-MS showedthe product had the expected M+H⁺ of 446.

Intermediate 61: 4-[2-(4-Chloro-pyrimidin-2-ylamino)-ethyl]-phenol: 2,4dichloropyrimidine (1.49 g) was dissolved in DMF along withdiisopropylethylmine (1.29 g) and tyramine (1.37 g.) The mixture wasstirred at room temperature overnight. The mixture was partitionedbetween ethyl acetate and water and the organic layer washed with 1 NHCl followed by saturated NaHCO₃ and brine. The solvent was removed andthe residue subjected to flash chromatography (ethyl acetate as eluent.)4-[2-(4-Chloro-pyrimidin-2-ylamino)-ethyl]-phenol eluted first and wasisolate as a minor product (15% yield.) LC-MS showed the product had theexpected M+H⁺ of 250.

Intermediate 62:1-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-ethanone:Intermediate 61 was coupled with 3-acetyl phenylboronic acid followingprocedure A. LC-MS showed the product had the expected M+H⁺ of 334.

Compound 121:4-(2-{4-[3-(1-Hydroxy-ethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 62 (0.96 g) was dissolved in methanol (30 mL) and treatedwith 0.5 g of sodium borohydride. The solvent was removed and theresidue partitioned between ethyl acetate and water. The residue waspurified by HPLC. LC-MS showed the product had the expected M+H⁺ of 336.¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at7.24 ppm) δ 8.31 (m, 1H) 8.05 (s, 1H) 7.4-7.6 (m, 3H) 7.09 (d, 2H) 6.99(d, 1H) 6.72 (d, 2H) 5.29 (t, 1H) δ 5.0 (q, 1H) 3.73 (q, 2H) 2.9 (t, 2H)1.52 (d, 3H).

Compound 122:4-(2-{4-[3-(Pyrazin-2-ylaminomethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 28 was coupled with 2-aminopyrazine following procedure B.LC-MS showed the product had the expected M+H⁺ of 399. ¹H NMR (Varian300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.3(m, 2H), 8.1 (m, 1H), 8.0 (m, 3H), 7.7 (m, 2H), 7.5 (m, 3H), 7.1 (m,2H), 6.7 (m, 2H), 4.6 (m, 2H), 3.6 (m, 2H), 2.8 (m, 2H).

Intermediate 63:[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-pyridin-3-yl-amine: Intermediate 1was coupled with 3-aminopyridine following procedure B. LC-MS showed theproduct had the expected M+H⁺ of 297.

Compound 123:4-(2-{4-[3-(Pyridin-3-ylaminomethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 63 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 398. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 9.2 (m, 1H),8.3 (s, 1H), 8.2 (m, 2H), 8.1 (m, 2H), 8.0 (m, 3H), 7.7 (s, 1H), 7.5 (d,2H), 7.1 (m, 4H), 6.6 (m, 2H), 4.2 (m, 1H), 3.2 (m, 2H), 2.7 (m, 2H).

Compound 124:(2-Morpholin-4-yl-ethyl)-{4-[3-(pyridin-3-ylaminomethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 63 was coupled with(2-Morpholin-4-yl-ethyl)-{4-[3-(pyridin-3-ylaminomethyl)-phenyl]-pyrimidin-2-yl}-aminefollowing procedure F. LC-MS showed the product had the expected M+H⁺ of398. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.3 (m, 2H), 8.1 (s, 1H), 7.9 (d, 1H), 7.5 (m, 2H), 7.1(m, 5H), 6.2 (d, 2H), 6.5 (m, 1H), 6.3 (m, 1H), 4.2 (m, 2H), 3.5 (m,4H), 3.4 (m, 2H), 2.4 (m, 4H).

Intermediate 64:N′-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-N,N-diethyl-propane-1,3-diamine:Intermediate 1 was coupled with N,N diethylpropanediamine followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 333.

Compound 125:4-[2-(4-{3-[(3-Diethylamino-propylamino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 64 was coupled with tyramine following procedure F. LC-MSshowed the product had the expected M+H⁺ of 434. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 1H),8.2 (m, 2H), 8.1 (m, 1H), 8.0 (m, 1H), 7.5 (m, 3H), 7.2 (m, 1H), 7.1 (m,4H), 6.6 (m, 2H), 4.2 (m, 1H), 3.5 (m, 2H), 2.7 (m, 3H), 2.6 (m, 6H),1.7 (m, 2H), 1.0 (m, 6H).

Compound 126:4-{2-[4-(3-{[(3-Diethylamino-propyl)-ethyl-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Compound 125 was coupled with acetaldehyde following procedure E. LC-MSshowed the product had the expected M+H⁺ of 462. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1),8.1 (m, 1), 8.0 (m, 2H), 7.5 (m, 2H), 71 (m, 3H), 6.7 (m, 2H), 4.9 (s,1H), 3.8 (s, 1H), 3.6 (m, 3H), 3.0 (m, 6H), 2.8 (m, 3H), 2.6 (m, 4H),1.8 (m, 2H), 1.2 (m, 9H).

Intermediate 65: [3-(2-Chloro-pyrimidin-4-yl)-benzyl]-isopropyl-amine:Intermediate 2 was coupled with isopropylamine following procedure B.LC-MS showed the product had the expected M+H⁺ of 262.

Compound 127:4-(2-{4-[3-(Isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 65 was coupled with tyramine following procedure F. Theproduct was purified by HPLC. LC-MS showed the product had the expectedM+H⁺ of 363. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to thesolvent peak at 7.24 ppm) δ 8.3 (m, 1H), 8.2 (m, 2H), 8.1 (m, 2H), 7.5(d, 2H), 7.2 (m, 2H), 7.1 (d, 1H), 7.0 (d, 2H), 6.7 (d, 2H), 3.8 (m,1H), 3.3 (m, 4H), 2.7 (m, 1H), 1.1 (m, 6H).

Intermediate 66:3-(R)-[Ethyl-(3-{2-[2-(3-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-carbamoyl]-piperidine-1-carboxylicacid tert-butyl ester: compound 96 was coupled with(R)-(−)-N-boc-nipecotic acid following procedure K and purified bychromatography on silica gel using MeOH:methylene chloride (2:98) aseluent. LC-MS showed the product had the expected M+H⁺ of 562. ¹H NMR(Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm)δ 8.3 (m, 1H), 7.9 (m, 2H) 7.4 (m, 2H) 7.3 (m, 1H) 7.0 (m, 4H) 4.7 (m,1H) 4.2 (m, 2H) 3.8 (m, 2H) 3.4 (m, 2H) 3.0 (m, 4H) 2.7 (m, 2H) 1.8 (m,4H) 1.5 (s, 6H) 1.4 (s, 3H) 1.2 (m, 3H).

Compound 128: Piperidine-3-(R)-carboxylic acidethyl-(3-{2-[2-(3-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-amide:Intermediate 66 was deprotected following procedure G2. LC-MS showed theproduct had the expected M+H⁺ of 462. ¹H NMR (Varian 300 MHz, CD₃ODshifts relative to the solvent peak at 3.3 ppm) δ 8.3 (m, 1H), 8.2 (s,2H) 7.6 (m, 3H) 7.3 (m, 1H) 7.1 (m, 2H) 6.9 (m, 1H) 4.7 (m, 1H) 4.0 (m,2H) 3.7 (m, 2H) 3.2 (m, 4H) 3.1 (m, 4H) 1.9 (m, 4H) 1.3 (m, 3H).

Intermediate 67:3-(S)-[Ethyl-(3-{2-[2-(3-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-carbamoyl]-piperidine-1-carboxylicacid tert-butyl ester: compound 96 was coupled with(S)-(+)-N-boc-nipecotic acid following procedure K and purified bychromatography on silica gel using MeOH:methylene chloride (2:98) aseluent. LC-MS showed the product had the expected M+H⁺ of 562. ¹H NMR(Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm)δ 8.3 (m, 1H), 7.9 (m, 2H) 7.4 (m, 2H) 7.3 (m, 1H) 7.0 (m, 4H) 4.7 (m,1H) 4.2 (m, 2H) 3.8 (m, 2H) 3.4 (m, 2H) 3.0 (m, 4H) 2.7 (m, 2H) 1.8 (m,4H) 1.5 (s, 6H) 1.4 (s, 3H) 1.2 (m, 3H).

Compound 129: Piperidine-3-(S)-carboxylic acidethyl-(3-{2-[2-(3-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-amide:Intermediate 67 was deprotected following procedure G2. LC-MS showed theproduct had the expected M+H⁺ of 462. ¹H NMR (Varian 300 MHz, CD₃ODshifts relative to the solvent peak at 3.3 ppm) δ 8.3 (m, 1H), 8.2 (s,2H) 7.6 (m, 3H) 7.3 (m, 1H) 7.1 (m, 2H) 6.9 (m, 1H) 4.7 (m, 1H) 4.0 (m,2H) 3.7 (m, 2H) 3.2 (m, 4H) 3.1 (m, 4H) 1.9 (m, 4H) 1.3 (m, 3H).

Intermediate 68:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with4-boc-2-(S)-methyl-piperazine following procedure B. LC-MS showed theproduct had the expected M+H⁺ of 403. ¹H NMR (Varian 300 MHz, CDCl₃,shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (d, 1H) 8.0 (m,2H) 7.6 (d, 1H) 7.5 (m, 2H) 4.8 (d, 1H) 4.1 (m, 1H) 3.6 (m, 2H) 3.3 (m,1H) 3.0 (m, 2H) 2.5 (m, 2H) 1.4 (s, 9H) 1.1 (m, 3H).

Intermediate 69:4-(3-{2-[2-(3-Fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-3-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 68 was coupled with3-fluorophenethylamine following procedure F. LC-MS showed the producthad the expected M+H⁺ of 506. ¹H NMR (Varian 300 MHz, CDCl₃, shiftsrelative to the solvent peak at 7.24 ppm) δ 8.4 (m, 2H) 8.0 (m, 1H) 7.7(m, 1H) 7.5 (m, 2H) 7.0 (m, 4H) 5.3 (m, 1H) 3.9 (m, 4H) 3.7 (m, 4H) 3.0(m, 4H) 1.6 (m, 3H) 1.4 (s, 9H).

Compound 130:[2-(3-Fluoro-phenyl)-ethyl]-{4-[3-(2-(S)-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 69 was deprotected following procedure G2. LC-MS showed theproduct had the expected M+H⁺ of 406. ¹H NMR (Varian 300 MHz, CD₃ODshifts relative to the solvent peak at 3.3 ppm) δ 8.7 (s, 1H) 8.4 (m,2H) 7.9 (d, 1H) 7.7 (m, 2H) 7.3 (m, 1H) 7.1 (d, 2H) 6.9 (m, 1H) 5.1 (m,1H) 4.4 (m, 1H) 4.0 (m, 2H) 3.7 (m, 5H) 3.5 (m, 2H) 3.1 (m, 2H) 1.7 (d,3H).

Compound 131:4-{2-[4-(3-Ethylaminomethyl-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol;Intermediate 28 was coupled with ethylamine following procedure B. LC-MSshowed the product had the expected M+H⁺ of 349. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (d, 1H)7.9 (m, 2H) 7.4 (m, 2H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.2 (m, 1H)3.9 (s, 2H) 3.7 (m, 2H) 2.8 (m, 2H) 2.7 (m, 2H) 1.2 (m, 3H).

Intermediate 70: [3-(2-Chloro-pyrimidin-4-yl)-benzyl]-isopropyl-carbamicacid tert-butyl ester: Intermediate 63 was treated with 1.3 eq. ofdi-tert-butyl dicarbonate and 1.5 eq. of N,N-diisopropylethylamine inmethylene chloride for 5 hours. The mixture was washed with water,brine, dried with anhydrous Na₂SO₄, and purified by chromatography(EtOAc:Hexane=10:90). LC-MS showed the product had the expected M+H⁺ of362. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.6 (d, 1H) 8.0 (s, 1H) 7.9 (d, 1H) 7.6 (d, 1H) 7.4 (m,2H) 4.4 (s, 2H) 1.4 (s, br, 10H) 1.1 (d, 6H).

Intermediate 71: 4-(2-Amino-ethyl)-2-chloro-phenol: 0.1 mol of2-(4-Methoxy-phenyl)-ethylamine was dissolved in 200 ml of acetic acid,followed by addition of 1.5 eq. of sulfuryl chloride at 0° to 5° C. Thesolution was stirred at room temperature for 1 hour. 250 ml of ether wasadded and the resulted solid was collected by filtration. The solid washeated in 48% aqueous HBr at 135° C. for 4 hours, cooled to 0° C., andthe crystal was collected by filtration and washed with small amount ofmethanol then with ethyl acetate. LC-MS showed the product as HBr salthad the expected M+H⁺ of 186. ¹H NMR (Varian 300 MHz, CD₃OD shiftsrelative to the solvent peak at 3.3 ppm) δ 7.2 (d, 1H) 7.0 (m, 1H) 6.9(d, 1H) 3.1 (m, 2H) 2.9 (m, 2H).

Intermediate 72:(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-isopropyl-carbamicacid tert-butyl ester: Intermediate 70 was coupled with Intermediate 71following procedure F. LC-MS showed the product had the expected M+H⁺ of497. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.3 (d, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.2 (m, 2H) 7.0 (m,3H) 4.4 (s, 2H) 3.7 (m, 2H) 2.8 (m, 2H) 1.4 (s, br, 10H) 1.0 (d, 6H).

Compound 132:2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 72 was deprotected following procedure G2. LC-MS showed theproduct had the expected M+H⁺ of 397. ¹H NMR (Varian 300 MHz, CD₃ODshifts relative to the solvent peak at 3.3 ppm) δ 8.4 (s, 1H) 8.3 (m,2H) 7.8 (d, 1H) 7.7 (m, 1H) 7.6 (d, 1H) 7.3 (d, 1H) 7.1 (d, 1H) 6.8 (d,1H) 4.4 (s, 2H) 3.8 (m, 2H) 3.6 (m, 1H) 3.0 (m, 2H) 1.4 (d, 6H).

Intermediate 73:2-(S)-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-propan-1-ol:Intermediate 1 was coupled with 2-(S)-amino-propan-1-ol followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 278. ¹HNMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24ppm) δ 8.4 (m, 1H) 7.8 (s, 1H) 7.7 (m, 1H) 7.5 (m, 1H) 7.3 (m, 1H) 7.0(m, 1H) 3.8 (m, 1H) 3.6 (m, 1H) 3.4 (m, 1H) 3.1 (m, 1H) 2.6 (m, 1H) 0.9(m, 3H).

Intermediate 74:{[[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-(2-hydroxy-1-methyl-ethyl)-carbamoyl]-methyl}-methyl-carbamicacid tert-butyl ester: Intermediate 73 was coupled with(tert-butoxycarbonyl-methyl-amino)-acetic acid following procedure K.LC-MS showed the product had the expected M+H⁺ of 449. ¹H NMR (Varian300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.6(m, 1H) 8.1 (m, 1H) 8.0 (m, 1H) 7.7 (m, 1H) 7.5 (m, 2H) 4.6 (m, 2H) 4.3(m, 2H) 4.0 (m, 1H) 3.7 (s, 1H) 3.5 (s, 1H) 3.0 (m, 4H) 1.4 (m, 9H) 1.2(m, 3H).

Intermediate 75:N-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-N-(2-hydroxy-1-methyl-ethyl)-2-methylamino-acetamide:Intermediate 73 was deprotected following procedure G2. LC-MS showed theproduct had the expected M+H⁺ of 349. ¹H NMR (Varian 300 MHz, CD₃ODshifts relative to the solvent peak at 3.3 ppm) δ 8.7 (m, 1H) 8.1 (m,3H) 7.6 (m, 2H) 4.7 (m, 2H) 4.4 (m, 1H) 3.8 (m, 1H) 3.7 (m, 3H) 2.8 (m,2H) 2.1 (m, 1H) 1.6 (m, 1H) 1.3 (m, 1H) 1.2 (m, 1H).

Intermediate 76:1-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-4,6-dimethyl-piperazin-2-one:Intermediate 75 was cyclized following procedure L. LC-MS showed theproduct had the expected M+H^(f) of 331. ¹H NMR (Varian 300 MHz, CDCl₃,shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (m, 1H) 8.0 (m,2H) 7.5 (m, 3H) 5.3 (m, 1H) 4.3 (m, 1H) 3.4 (m, 2H) 3.1 (m, 1H) 2.5 (m,2H) 2.3 (s, 3H) 1.2 (d, 3H).

Compound 133:1-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-4,6-dimethyl-piperazin-2-one:Intermediate 76 was coupled with intermediate 71 following procedure F.LC-MS showed the product had the expected M+H⁺ of 466. ¹H NMR (Varian300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 8.3(m, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.2 (m, 1H) 7.0 (m, 3H) 5.6 (m, 1H) 5.3(d, 1H) 4.1 (d, 1H) 3.7 (m, 2H) 3.5 (m, 1H) 3.3 (d, 1H) 3.1 (d, 1H) 2.8(m, 2H) 2.5 (m, 2H) 2.3 (s, 3H) 1.3 (d, 3H).

Intermediate 77:4-{[3-(2-Chloro-5-fluoro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-piperidine-1-carboxylicacid tert-butyl ester: Made by procedure O. LC-MS showed the product hadthe expected M+H⁺ of 499.

Compound 134:N-(3-{5-Fluoro-2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 77 was coupled with tyramine following procedure Q. Theresulting product was deprotected following procedure R. LC-MS showedthe product had the expected M+H⁺ of 500. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.23 (d, 1H), 8.16 (s,1H), 7.96 (d, 1H), 7.48 (m, 2H), 7.05 (d, 2H), 6.69 (d, 2H), 4.54 (s,2H), 3.90 (m, 1H), 3.56 (t, 2H), 3.34 (m, 2H), 3.00 (s, 3H), 2.91 (m,2H), 2.80 (t, 2H), 1.84 (m, 4H).

Compound 135:4-[(3-{5-Fluoro-2-[2-(3-fluoro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 77 was coupled with intermediate 83following procedure Q. LC-MS showed the product had the expected M+H⁺ of618. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.19 (d, 1H), 8.01 (s, 1H), 7.93 (d, 1H), 7.43 (m, 2H),6.84 (m, 3H), 5.77 (s, 1H), 5.07 (t, 1H), 4.44 (s, 2H), 4.02 (m, 2H),3.84 (m, 1H), 3.63 (q, 2H), 2.87 (m, 2H), 2.83 (s, 3H), 2.64 (t, 2H),1.59 (m, 4H), 1.39 (s, 9H).

Compound 136:N-(3-{5-Fluoro-2-[2-(3-fluoro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Compound 135 was deprotected following procedure R. LC-MS showed theproduct had the expected M+H⁺ of 518. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.26 (d, 1H), 8.18 (s,1H), 7.97 (d, 1H), 7.48 (m, 2H), 7.08 (m, 2H), 6.78 (m, 1H), 4.54 (s,2H), 3.92 (m, 1H), 3.60 (t, 2H), 3.32 (m, 2H), 3.03 (s, 3H), 2.95 (m,2H), 2.80 (t, 2H), 1.88 (m, 4H).

Compound 137:N-(3-{5-Fluoro-2-[2-(3-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 77 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure Q. The resulting product was deprotected followingprocedure R. LC-MS showed the product had the expected M+H⁺ of 502. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.26 (d, 1H), 8.19 (s, 1H), 7.98 (d, 1H), 7.49 (m, 2H), 7.08 (m,3H), 6.87 (m, 1H), 4.55 (s, 2H), 3.91 (m, 1H), 3.64 (t, 2H), 3.34 (m,2H), 3.03 (s, 3H), 3.00 (m, 2H), 2.92 (t, 2H), 1.91 (m, 4H).

Compound 138:N-(3-{5-Fluoro-2-[2-(4-hydroxy-3-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 77 was coupled with 4-(2-amino-ethyl)-2-methoxy-phenolfollowing procedure Q. The resulting product was deprotected followingprocedure R. LC-MS showed the product had the expected M+H⁺ of 530. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.25 (d, 1H), 8.14 (s, 1H), 7.97 (d, 1H), 7.48 (m, 2H), 6.82 (s,1H), 6.69 (s, 2H), 4.54 (s, 2H), 3.91 (m, 1H), 3.80 (s, 3H) 3.60 (t,2H), 3.32 (m, 2H), 3.03 (s, 3H), 2.94 (m, 2H), 2.81 (t, 2H), 1.87 (m,4H).

Compound 139:N-(3-{2-[2-(3-Chloro-phenyl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 77 was coupled with 2-(3-chloro-phenyl)-ethylaminefollowing procedure Q. The resulting product was deprotected followingprocedure R. LC-MS showed the product had the expected M+H⁺ of 518. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.25 (d, 1H), 8.18 (s, 1H), 7.97 (d, 1H), 7.49 (m, 2H), 7.15 (m,4H), 4.56 (s, 2H), 3.93 (m, 1H), 3.64 (t, 2H), 3.33 (m, 2H), 3.04 (s,3H), 2.98 (m, 2H), 2.91 (t, 2H), 1.91 (m, 4H).

Compound 140:N-[3-(5-Fluoro-2-phenethylamino-pyrimidin-4-yl)-benzyl]-N-piperidin-4-yl-methanesulfonamide:Intermediate 77 was coupled with phenethylamine following procedure Q.The resulting product was deprotected following procedure R. LC-MSshowed the product had the expected M+H⁺ of 484. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H),8.17 (s, 1H), 7.98 (d, 1H), 7.49 (m, 2H), 7.26 (m, 5H), 4.55 (s, 2H),3.89 (m, 1H), 3.62 (t, 2H), 333 (m, 2H), 3.03 (s, 3H), 2.98 (m, 2H),2.90 (t, 2H), 1.89 (m, 4H).

Compound 141:4-[(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-benzyl)-methanesulfonyl-amino]-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 77 was coupled with intermediate 71following procedure Q. LC-MS showed the product had the expected M+H⁺ of634. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 8.20 (d, 1H), 8.03 (s, 1H), 7.94 (d, 1H), 7.43 (m, 2H),7.19 (s, 1H), 6.89 (m, 2H), 5.71 (s, 1H), 5.08 (t, 1H), 4.45 (s, 2H),4.02 (m, 2H), 3.81 (m, 1H), 3.63 (q, 2H), 2.83 (s, 3H), 2.81 (m, 2H),2.63 (t, 2H), 1.51 (m, 4H), 1.39 (s, 9H).

Compound 142:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Compound 141 was deprotected following procedure R. LC-MS showed theproduct had the expected M+H⁺ of 534. 1H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H), 8.17 (s,1H), 7.97 (d, 1H), 7.49 (m, 2H), 7.18 (d, 1H), 6.99 (d, 1H), 6.79 (d,1H), 4.55 (s, 2H), 3.91 (m, 1H), 3.58 (t, 2H), 3.34 (m, 2H), 3.03 (s,3H), 2.95 (m, 2H), 2.80 (t, 2H), 1.87 (m, 4H).

Intermediate 78:(3-{[3-(2-Chloro-5-fluoro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-propyl)-carbamicacid tert-butyl ester: Made by procedure P. LC-MS showed the product hadthe expected M+H⁺ of 423.

Compound 143:4-{2-[4-(3-{[(3-Amino-propyl)-ethyl-amino]-methyl}-phenyl)-5-fluoro-pyrimidin-2-ylamino]-ethyl}-2-fluoro-phenol:Intermediate 78 was coupled with intermediate 83 following procedure Q.The resulting product was deprotected following procedure R. LC-MSshowed the product had the expected M+H⁺ of 442. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.29 (d, 1H),8.18 (s, 2H), 7.66 (m, 2H), 6.77 (m, 3H), 4.49 (s, 2H), 3.59 (t, 2H),3.24 (m, 4H), 2.98 (t, 2H), 2.80 (t, 2H), 2.07 (m, 2H), 1.36 (t, 3H).

Compound 144:N1-Ethyl-N1-(3-{5-fluoro-2-[2-(3-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-propane-1,3-diamine:Intermediate 78 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure Q. The resulting product was deprotected followingprocedure R. LC-MS showed the product had the expected M+H⁺ of 426. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.29 (d, 1H), 8.19 (s, 2H), 7.66 (m, 2H), 6.97 (m, 4H), 4.49 (s,2H), 3.64 (t, 2H), 3.24 (m, 4H), 2.97 (t, 2H), 2.92 (t, 2H), 2.07 (m,2H), 1.36 (t, 3H).

Compound 145:N1-(3-{2-[2-(3-Chloro-phenyl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-benzyl)-N1-ethyl-propane-1,3-diamine:Intermediate 78 was coupled with 2-(3-chloro-phenyl)-ethylaminefollowing procedure Q. The resulting product was deprotected followingprocedure R. LC-MS showed the product had the expected M+H⁺ of 442. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.30 (d, 1H), 8.18 (s, 2H), 7.66 (m, 2H), 7.12 (m, 4H), 4.49 (s,2H), 3.63 (t, 2H), 3.24 (m, 4H), 2.98 (t, 2H), 2.90 (t, 2H), 2.08 (m,2H), 1.36 (t, 3H).

Compound 146:4-{2-[4-(3-{[(3-Amino-propyl)-ethyl-amino]-methyl}-phenyl)-5-fluoro-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 78 was coupled with tyramine following procedure Q. Theresulting product was deprotected following procedure R. LC-MS showedthe product had the expected M+H⁺ of 424. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.29 (d, 1H), 8.19 (s,2H), 7.66 (m, 2H), 7.05 (d, 2H), 6.68 (d, 2H), 4.49 (s, 2H), 3.58 (t,2H), 3.24 (m, 4H), 2.98 (t, 2H), 2.80 (t, 2H), 2.07 (m, 2H), 1.36 (t,3H).

Compound 147:4-{2-[4-(3-{[(3-Amino-propyl)-ethyl-amino]-methyl}-phenyl)-5-fluoro-pyrimidin-2-ylamino]-ethyl}-2-chloro-phenol:Intermediate 78 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure Q. The resulting product was deprotected followingprocedure R. LC-MS showed the product had the expected M+H⁺ of 458. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.28 (d, 1H), 8.17 (s, 2H), 7.66 (m, 2H), 7.17 (d, 1H), 6.97 (d,1H), 6.78 (d, 1H), 4.48 (s, 2H), 3.59 (t, 2H), 3.24 (m, 4H), 2.98 (t,2H), 2.79 (t, 2H), 2.06 (m, 2H), 1.36 (t, 3H).

Intermediate 79:4-[2-(3-{5-Fluoro-2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-ethyl]-piperidine-1-carboxylicacid tert-butyl ester: Made by procedure U. LC-MS showed the product hadthe expected M+H⁺ of 521.

Compound 148:4-(2-{5-Fluoro-4-[3-(2-piperidin-4-yl-ethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 79 was coupled with tyramine following procedure I. Theresulting product was deprotected following procedure J. LC-MS showedthe product had the expected M+H⁺ of 421. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.23 (d, 1H), 7.91 (s,1H), 7.85 (d, 1H), 7.32 (m, 2H), 7.06 (d, 2H), 6.68 (d, 2H), 3.54 (t,2H), 3.35 (m, 2H), 2.89 (t, 2H), 2.73 (m, 4H), 1.97 (d, 2H), 1.61 (m,3H), 1.32 (m, 2H).

Compound 149:2-Chloro-4-(2-{5-fluoro-4-[3-(2-piperidin-4-yl-ethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 79 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure I. The resulting product was deprotected followingprocedure J. LC-MS showed the product had the expected M+H⁺ of 455. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.23 (d, 1H), 7.90 (s, 1H), 7.85 (d, 1H), 7.35 (m, 2H), 7.20 (s,1H), 6.99 (d, 1H), 6.80 (d, 1H), 3.56 (t, 2H), 3.34 (m, 2H), 2.89 (t,2H), 2.72 (m, 4H), 1.97 (d, 2H), 1.60 (m, 3H), 1.32 (m, 2H).

Intermediate 80: 2-(3,5-Difluoro-phenyl)-ethylamine: 3,5difluorophenylacetonitrile (5 g) was dissolved in TI-IF (100 mL) and asolution of BH3 in THF (200 mL of 1 M) was added dropwise. The mixturewas refluxed overnight, cooled in an ice bath, and the reaction quenchedwith methanol (20 mL). The solvent was removed by rotary evaporation andthe residue partitioned between ethyl acetate and water. The organiclayer was washed with sat NaCl and the solvent again removed to giveproduct, which was used in the next step without purification.

Compound 150:[2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 7 was coupled with intermediate 80 following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 408. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.5 (m, 1H)7.3-7.6 (m, 6H) 7.05 (m, 1H) 6.92 (m, 1H) 6.75 (m, 1H) 3.9 (br s, 2H)3.75 (m, 1H) 3.45 (m, 3H) 3.18 (m, 2H) 3.05 (m, 2H) 2.27 (m, 3H) 1.77(m, 2H).

Intermediate 81: 2-Fluoro-1-methoxy-4-(2-nitro-vinyl)-benzene:3-Fluoro-4-methoxy-benzaldehyde (10 g) was dissolved in 100 mL ofnitromethane along with 5 g of ammonium acetate. The mixture wasrefluxed for 2 hours. The nitromethane was removed by rotary evaporationand the residue recrystallized from ethanol to give 7.6 g of theexpected product. LC-MS showed the product had the expected M+H⁺ of 198.

Intermediate 82: 2-(3-Fluoro-4-methoxy-phenyl)-ethylamine: Lithiumaluminum hydride (200 mL of 1 M in diethyl ether) was placed in a 1 Lround bottomed flask along with 300 mL of diethyl ether. Intermediate 81was placed in the thimble of a soxhlet extractor atop this flask and themixture refluxed for 24 hours. The mixture was cooled to 0° C. and 50 mLof ethyl acetate added dropwise. After stirring for 1 hour, the mixturewas quenched with 100 mL of 1 N KHSO₄. The Organic layer was separatedwashed with sat. NaHCO₃, sat. NaCl, and dried over MgSO₄. Removal of thesolvent gave product. LC-MS showed the product had the expected M+H⁺ of170. It was used in the next step without purification.

Intermediate 83: 4-(2-Amino-ethyl)-2-fluoro-phenol: Intermediate 82 wasdissolved in 200 mL of 48% aqueous HBr and the mixture heated to refluxfor 2 hours. The Solvent was removed by rotary evaporation. The residuewas taken up in 100 mL of ethanol and the solvent again removed. Thiswas repeated twice more to remove residual water. LC-MS showed theproduct was >90% pure had the expected M+H⁺ of 156.

Compound 151:2-Fluoro-4-(2-{4-[3-(piperidin-4-ylamino)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 7 was coupled with intermediate 83 following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 408.

Intermediate 84:4-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with4-Amino-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. When the starting aldehyde had been consumed, 2 equivalentseach of acetaldehyde and sodium triacetoxyborohydride were added and themixture stirred for another two hours. The organic layer was washedwith, water followed by sat. NaCl. The solvent was removed to giveproduct LC-MS showed the product was >90% pure and had the expected M+H⁺of 403, and it was used in the following reactions without purification.

Compound 152:[2-(3,5-Difluoro-phenyl)-ethyl]-(4-{3-[(ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-amine:Intermediate 84 was coupled with intermediate 80 following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 452. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.3-8.4 (m,3H), 7.6-7.9 (m, 2H) 7.45 (d, 1H) 7.2 (m, 1H) 6.92 (m, 2H) 6.75 (m, 1H)4.56 (br s, 2H) 3.88 (m, 3H) 3.62 (m, 2H) 3.15 (m, 1H) 3.05 (m, 2H) 2.47(m, 2H) 2.2 (m, 2H) 1.33 (t, 3H).

Compound 153: 2-Chloro-4-(2-{4-[3-(2-(S)methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenolIntermediate 68 was coupled with intermediate 71 following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 438. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.55 (s, 1H)8.28 (d, 1H) 8.1 (s, 1H) 7.99 (d, 1H) 7.5 (m, 2H) 7.29 d, 1H) 7.1 (d,1H) 7.0 (m, 1H) 6.82 (m, 1H) 4.2 (d, 1H) 3.62 (t, 1H) 3.38 (m, 4H) 3.2(m, 1H) 3.0 (m, 1H) 2.85 (m, 3H) 2.7 (m, 1H) 2.35 (m, 1H) 1.28 (d, 3H).

Compound 154: [2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(2-(S)methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine: Intermediate68 was coupled with intermediate 80 following procedure F. The resultingproduct was deprotected following procedure G. LC-MS showed the producthad the expected M+H⁺ of 424. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.30 ppm) δ 8.38 (m, 2H) 8.36 (d, 2H)7.8 (m, 1H) 7.68 (m, 1H) 7.5 (d, 1H) 6.95 (m, 2) 6.75 (m, 1H) 4.75 (d,1H) 4.02 (d, 1H) 3.9 (br s, 2H) 3.4-3.65 (m, 3H) 3.2-3.4 (m, 4H) 3.05(m, 3H) 1.55 (d, 3H).

Compound 155:(4-{3-[(Ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-[2-(3-fluoro-phenyl)-ethyl]-amine:Intermediate 84 was coupled with 3-fluoro phenethylamine followingprocedure F. The resulting product was deprotected following procedureG. The product was purified by HPLC. LC-MS showed the product had theexpected M+H⁺ of 434. ¹H NMR (Varian 300 MHz, DMSO, shifts relative tothe solvent peak at 2.50 ppm) δ 8.3 (d, 1H), 8.0 (s, 1H), 7.9 (d, 1H),7.4 (m, 2H), 7.3 (m, 2H), 7.1 (d, 2H), 7.0 (d, 1H), 3.6 (s, 2H), 3.2 (m,2H), 2.9 (m, 6H), 2.7 (q, 2H), 1.8-1.7 (m, 5H), 0.96 (t, 3H).

Compound 156:(N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-(1-ethyl-piperidin-4-yl)methanesulfonamide:Compound 169 was coupled with acetaldehyde following procedure E. Theproduct was purified by HPLC. LC-MS showed the product had the expectedM+H⁺ of 544. ¹H NMR (Varian 300 MHz, DMSO, shifts relative to thesolvent peak at 2.50 ppm) δ 8.3 (d, 1H), 8.1 (d, 1H), 7.5-7.4 (m, 3H),7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 4.4 (s, 2H), 3.6 (d,2H), 3.5 (d, 2H), 3.0 (s, 3H), 2.8 (q, 2H), 2.2 (m, 1H), 1.8 (m, 4H),1.6 (m, 4H), 0.96 (t, 3H).

Compound 157:(N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-(1-propyl-piperidin-4-yl)methanesulfonamide:Compound 169 was coupled with propionaldehyde following procedure E. Theproduct was purified by HPLC. LC-MS showed the product had the expectedM+H⁺ of 558. ¹H NMR (Varian 300 MHz, DMSO, shifts relative to thesolvent peak at 2.50 ppm) δ 8.3 (d, 1H), 8.1 (d, 1H), 7.5-7.4 (m, 3H),7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 4.4 (s, 2H), 3.6 (d,2H), 3.5 (d, 2H), 3.0 (s, 3H), 2.7 (m, 1H), 2.1 (t, 2H), 1.8 (m, 4H),1.6 (m, 4H), 1.3 (q, 2H), 0.76 (t, 3H).

Intermediate 85:2-Chloro-4-[2-(4-{3-[(ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 84 was coupled with intermediate 71 following procedure F.The resulting product was deprotected by procedure G. LC-MS showed theproduct had the expected M+H⁺ of 466.

Compound 158:2-Chloro-4-{2-[4-(3-{[ethyl-(-ethyl-piperidin-4-yl)-amino}-methyl]-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 85 was coupled with acetaldehyde following procedure E. Theproduct was purified by HPLC. LC-MS showed the product had the expectedM+H⁺ of 494. ¹H NMR (Varian 300 MHz, DMSO, shifts relative to thesolvent peak at 2.50 ppm) δ 8.3 (d, 1H), 7.9 (d, 1H), 7.5-7.4 (m, 3H),7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 3.6 (s, 2H), 3.5 (d,2H), 3.1 (d, 2H), 2.7 (q, 2H), 2.6 (m, 3H), 2.3 (m, 4H), 1.7-1.6 (m,4H), 1.0 (t, 3H), 0.94 (t, 3H).

Compound 159:2-Chloro-4-{2-[4-(3-{[ethyl-(1-propyl-piperidin-4-yl)-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 85 was coupled with propionaldehyde following procedure E.The product was purified by HPLC. LC-MS showed the product had theexpected M+H⁺ of 508. ¹H NMR (Varian 300 MHz, DMSO, shifts relative tothe solvent peak at 2.50 ppm) δ 8.3 (d, 1H), 7.9 (d, 1H), 7.5-7.4 (m,3H), 7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 3.6 (s, 2H),3.5 (d, 2H), 3.1 (d, 2H), 2.7 (q, 2H), 2.6 (m, 3H), 2.3 (m, 4H), 1.7-1.6(m, 4H), 1.5-1.4 (m, 2H), 0.94 (t, 3H), 0.80 (t, 3H).

Compound 160:2-Chloro-4-{2-[4-(3-{[ethyl-(1-pyridin-4-ylmethyl-piperidin-4-yl)-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 85 was coupled with pyridine 4-carboxaldehyde followingprocedure E. The product was purified by HPLC. LC-MS showed the producthad the expected M+H⁺ of 557. ¹H NMR (Varian 300 MHz, DMSO, shiftsrelative to the solvent peak at 2.50 ppm) δ 8.4 (d, 2H), 8.2 (d, 1H),8.1 (s, 1H), 7.8 (d, 1H), 7.4-7.3 (m, 2H), 7.2-7.1 (m, 3H), 7.0 (d, 1H),6.9 (d, 1H), 6.8 (d, 1H), 3.6 (s, 4H), 3.4 (d, 2H), 3.1 (d, 2H), 2.7 (m,3H), 1.9-1.8 (m, 4H), 1.6-1.4 (m, 4H), 0.94 (t, 3H).

Intermediate 86: 5-(2-Chloro-pyrimidin-4-yl)-2-methoxy-benzaldehyde: 2,4dichloropyrimidine and 3-formyl 4-methoxy phenyl boronic acid werecoupled following procedure A. LC-MS showed the product was >95% pureand had the expected M+H⁺ of 249.

Intermediate 87:4-[5-(2-Chloro-pyrimidin-4-yl)-2-methoxy-benzylamino]-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 86 was coupled with4-Amino-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product was >95% pure and had the expectedM+H⁺ of 433.

Intermediate 88:4-{[5-(2-Chloro-pyrimidin-4-yl)-2-methoxy-benzyl]-methanesulfonyl-amino}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 88 was coupled with methanesulfonylchloride following procedure D. LC-MS showed the product was >95% pureand had the expected M+H⁺ of 511.

Compound 161:N-(5-{2-[2-(3-Fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 88 was coupled with 3-fluorophenethylamine followingprocedure F. The resulting product was deprotected following procedureG. The product was purified by HPLC. LC-MS showed the product had theexpected M+H⁺ of 514. ¹H NMR (Varian 300 MHz, DMSO, shifts relative tothe solvent peak at 2.50 ppm) δ 7.9 (d, 1H), 7.3 (m, 2H), 7.1 (t, 1H),7.0 (m, 3H), 6.8 (d, 2H), 4.3 (s, 2H), 3.9 (s, 3H), 3.5 (d, 2H), 3.0 (s,3H), 2.9 (m, 6H), 2.6 (m, 1H), 1.8-1.6 (m, 4H).

Compound 162:(N-[2-Methoxy-5-(2-phenylethylamino-pyrimidin-4-yl)-benzyl]-N-piperidin-4-yl-methanesulfonamide:Intermediate 88 was coupled with phenethylamine. The product waspurified by HPLC. LC-MS showed the product had the expected M+H⁺ of 496.¹H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at2.50 ppm) δ 7.9 (d, 1H), 7.3-7.2 (m, 4H), 7.2-7.0 (m, 3H), 6.9 (d, 2H),4.3 (s, 2H), 3.9 (s, 3H), 3.5 (d, 2H), 3.0 (s, 3H), 2.8 (m, 6H), 2.6 (m,1H), 1.7-1.5 (m, 4H).

Compound 163:(N-(5-{2-[2-(3-Fluoro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 88 was coupled with intermediate 83 following procedure F.The resulting product was deprotected following procedure G. The productwas purified by HPLC. LC-MS showed the product had the expected M+H⁺ of530. ¹H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peakat 2.50 ppm) δ 7.9 (d, 1H), 7.0 (m, 2H), 7.0 (m, 3H), 6.8 (m, 2H), 4.3(s, 2H), 3.9 (s, 3H), 3.5 (d, 2H), 3.0 (s, 3H), 2.7 (m, 6H), 2.6 (m,1H), 1.7-1.5 (m, 4H).

Intermediate 89: 5-(2-Chloro-pyrimidin-4-yl)-2-fluoro-benzaldehyde: 2,4dichloropyrimidine and 3-formyl 4-fluorophenyl boronic acid were coupledfollowing procedure A. LC-MS showed the product was >95% pure and hadthe expected M+H⁺ of 237.

Intermediate 90:4-[5-(2-Chloro-pyrimidin-4-yl)-2-fluoro-benzylamino]-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 89 was coupled with4-Amino-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product was >95% pure and had the expectedM+H⁺ of 421.

Intermediate 91:4-{[5-(2-Chloro-pyrimidin-4-yl)-2-fluoro-benzyl]-methanesulfonyl-amino}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 90 was coupled with methanesulfonylchloride following procedure D LC-MS showed the product was >95% pureand had the expected M+H⁺ of 499.

Compound 164:N-(2-Fluoro-5-{2-[2-(3-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 91 was coupled with 3-fluorophenethylamine followingprocedure F. The resulting product was deprotected following procedureG. The product was purified by HPLC. LC-MS showed the product had theexpected M+H⁺ of 502. ¹H NMR (Varian 300 MHz, DMSO, shifts relative tothe solvent peak at 2.50 ppm) δ 8.0 (d, 1H), 7.3-7.2 (m, 3H), 7.1-6.9(m, 5H), 4.4 (s, 2H), 3.6 (d, 2H), 3.0 (s, 3H), 2.9 (m, 6H), 2.7 (m,1H), 1.7 (m, 4H).

Compound 165:(N-(2-Fluoro-5-{2-[2-(3-Fluoro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 91 was coupled with intermediate 83 following procedure F.The resulting product was deprotected following procedure G. The productwas purified by HPLC. LC-MS showed the product had the expected M+H⁺ of518. ¹H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peakat 2.50 ppm) δ 8.0 (d, 1H), 7.3-7.2 (m, 2H), 7.0 (m, 2H), 6.8 (m, 3H),4.4 (s, 2H), 3.5 (d, 2H), 3.0 (s, 3H), 2.8-2.6 (m, 7H), 1.7 (m, 4H).

Intermediate 92:4-[2-(4-{3-[(Ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-2-fluoro-phenol:Intermediate 84 was coupled with intermediate 83 following procedure F.The resulting product was deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 450.

Compound 166:4-{2-[4-(3-{[Ethyl-(1-propyl-piperidin-4-yl)-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-2-fluoro-phenol:Intermediate 92 was coupled with propionaldehyde following procedure E.The product was purified by HPLC. LC-MS showed the product had theexpected M+H⁺ of 492. ¹H NMR (Varian 300 MHz, DMSO, shifts relative tothe solvent peak at 2.50 ppm) δ 7.9 (d, 1H), 7.4-7.3 (m, 2H), 7.2 (t,1H), 7.0-6.9 (m, 2H), 6.8 (m, 3H), 3.6 (s, 2H), 3.5 (d, 2H), 3.1 (m,3H), 2.7 (q, 2H), 2.6 (m, 4H), 2.2 (t, 2H), 1.7-1.6 (m, 4H), 1.5-1.4 (m,2H), 0.94 (t, 3H), 0.80 (t, 3H).

Compound 167:4-{2-[4-(3-{[Ethyl-(1-pyridin-4-ylmethyl-piperidin-4-yl)-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-2-fluoro-phenol:Intermediate 92 was coupled with pyridine-4-carboxaldehyde followingprocedure E. The product was purified by HPLC. LC-MS showed the producthad the expected M+H⁺ of 541. ¹H NMR (Varian 300 MHz, DMSO, shiftsrelative to the solvent peak at 2.50 ppm) δ 8.4 (d, 2H), 8.3 (d, 1H),7.9 (d, 1H), 7.4 (m, 2H), 7.2 (m, 3H), 7.0 (m, 2H), 6.8 (m, 2H), 3.6 (s,2H), 3.5 (d, 2H), 3.4 (s, 2H), 2.7 (m, 4H), 2.5 (q, 2H), 1.9 (m, 1H),1.7-1.4 (m, 4H), 0.9 (t, 3H).

Compound 168:(N-(3-{2-[2-(3-Fluoro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl-methanesulfonamide:Intermediate 30 was coupled with intermediate 83 following procedure F.The resulting product was deprotected following procedure G. The productwas purified by HPLC. LC-MS showed the product had the expected M+H⁺ of500. ¹H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peakat 2.50 ppm) δ 8.1 (d, 1H), 7.9 (d, 1H), 7.5 (m, 2H), 7.2 (t, 1H), 7.0(m, 2H), 6.8 (d, 2H), 4.4 (s, 2H), 3.8 (d, 2H), 3.5 (d, 2H), 3.0 (s,3H), 2.7 (m, 4H), 2.6 (m, 1H), 1.7 (m, 4H).

Compound 169:(N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-piperidin-4-yl)methanesulfonamide:Intermediate 30 was coupled with intermediate 71 following procedure F.The resulting product was deprotected following procedure G. The productwas purified by HPLC. LC-MS showed the product had the expected M+H⁺ of516. ¹H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peakat 2.50 ppm) δ 8.3 (d, 1H), 7.9 (d, 1H), 7.4 (m, 2H), 7.2 (m, 2H), 7.0(d, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 4.4 (s, 2H), 3.8 (d, 2H), 3.5 (d,2H), 3.0 (s, 3H), 2.7 (m, 4H), 2.6 (m, 1H), 1.6 (m, 4H).

Intermediate 93:4-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-propyl-amino}-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 29 was coupled with propionaldehydefollowing procedure E. LC-MS showed the product had the expected M+H⁺ of445.

Compound 170:2-Fluoro-4-[2-(4-{3-[(piperidin-4-yl-propyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 93 was coupled with intermediate 83 following procedure F.The resulting product was deprotected following procedure G. The productwas purified by HPLC. LC-MS showed the product had the expected M+H⁺ of464. ¹H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peakat 2.50 ppm) δ 8.3 (d, 1H), 7.9 (d, 1H), 7.4 (m, 2H), 7.2 (t, 1H), 7.0(d, 2H), 6.9 (d, 1H), 6.8 (d, 1H), 3.6 (s, 2H), 3.5 (d, 2H), 3.2 (d,2H), 2.7 (m, 5H), 2.4 (t, 2H), 1.8 (m, 4H), 1.3 (q, 2H), 0.96 (t, 3H).

Compound 171:2-Chloro-4-[2-[4-{3-[(piperidin-4-yl)-propyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino]-ethyl]-phenol:Intermediate 93 was coupled with intermediate 71 following procedure F.The resulting product was deprotected following procedure G. The productwas purified by HPLC. LC-MS showed the product had the expected M+H⁺ of480. ¹H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peakat 2.50 ppm) δ 8.3 (d, 1H), 7.9 (d, 1H), 7.4 (m, 2H), 7.2 (m, 2H), 7.0(d, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 3.6 (s, 2H), 3.5 (d, 2H), 3.2 (d,2H), 2.7 (m, 5H), 2.4 (t, 2H), 1.8 (m, 4H), 1.3 (m, 2H), 0.7 (t, 3H).

Compound 172:[2-(3-Fluoro-phenyl)-ethyl-(4-{3-[(piperidin-4-yl-propyl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-amine:Intermediate 93 was coupled with 3-fluorophenethylamine followingprocedure F. The resulting product was deprotected following procedureG. The product was purified by HPLC. LC-MS showed the product had theexpected M+H⁺ of 448. ¹H NMR (Varian 300 MHz, DMSO, shifts relative tothe solvent peak at 2.50 ppm) δ 8.3 (d, 1H), 8.0 (s, 1H), 7.9 (d, 1H),7.4 (m, 2H), 7.3 (m, 2H), 7.1 (d, 2H), 7.0 (d, 1H), 3.6 (s, 2H), 3.5 (d,2H), 3.2 (d, 2H), 2.9 (m, 4H), 2.8 (m, 1H), 2.5 (d, 2H), 1.8 (m, 4H),1.3 (m, 2H), 0.96 (t, 3H).

Intermediate 94:4-{2-[3-(2-Chloro-pyrimidin-4-yl)-phenyl]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester: Made by Procedure U. LC-MS showed the product hadthe expected M+H⁺ of 402.

Compound 173:2-Chloro-4-(2-{4-[3-(2-piperidin-4-yl-ethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 94 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure Q. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 437. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.27 (d, 1H), 8.05 (s, 1H), 7.99 (m, 1H), 7.46 (d, 2H), 7.35 (d,1H), 7.24 (d, 1H), 7.03 (d, 1H), 6.80 (d, 1H), 3.70 (m, 2H), 3.35 (m,2H), 2.78 (m, 6H), 1.99 (d, 2H), 1.66 (m, 3H), 1.37 (m, 2H).

Compound 174:2-Chloro-4-[2-(4-{3-[(ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 84 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 467. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.27 (m, 2H), 7.69 (m, 2H), 7.26 (d, 1H), 7.19 (m, 1H), 7.04 (s,1H), 7.01 (d, 1H), 6.80 (d, 1H), 4.48 (m, 2H), 3.53 (m, 4H), 3.09 (m,4H), 2.85 (t, 2H), 2.39 (d, 2H), 2.03 (m, 3H), 1.32 (t, 3H).

Intermediate 95:3-({[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3-amino-methyl-piperidine-1-carboxylic acid tert-butyl ester followingprocedure B. The crude product was coupled with acetaldehyde followingprocedure E. LC-MS showed the product had the expected M+H⁺ of 444.

Compound 175:4-[2-(4-{3-[(Ethyl-piperidin-3(S)-ylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 95 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 447. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.66 (s, 1H), 8.38 (d,1H), 8.35 (s, 1H), 7.94 (d, 1H), 7.75 (t, 1H), 7.67 (d, 1H), 7.11 (d,2H), 6.68 (d, 2H), 4.57 (s, 2H), 3.94 (s, 2H), 3.13 (m, 2H), 2.82 (m,6H), 2.65 (t, 1H), 2.34 (m, 2H), 1.74 (m, 4H), 1.24 (t, 3H).

Intermediate 96: 5-(2-Chloro-pyrimidin-4-yl)-thiophene-2-carboxaldehyde:was made by procedure V. LC-MS showed the product had the expected M+H⁺of 225.

Intermediate 97:4-{[5-(2-Chloro-pyrimidin-4-yl)-thiophen-2-ylmethyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester was made from intermediate 96 by procedure B.LC-MS showed the product had the expected M+H⁺ of 409.

Intermediate 98:4-{[5-(2-Chloro-pyrimidin-4-yl)-thiophen-2-ylmethyl]-propyl-amino}-piperidine-1-carboxylicacid tert-butyl ester was made from intermediate 97 by procedure E.LC-MS showed the product had the expected M+H⁺ of 451.

Compound 176:2-Chloro-4-[2-(4-{5-[(piperidin-4-yl-propyl-amino)-methyl]-thiophen-2-yl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 98 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 487. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.18 (d, 1H), 7.98 (d, 1H), 7.37 (d, 1H), 7.26 (s, 1H), 7.23 (d,1H), 7.01 (d, 1H), 6.80 (d, 1H), 4.49 (s, 2H), 3.70 (s, 2H), 3.44 (m,3H), 2.97 (m, 4H), 2.85 (t, 2H), 2.27 (d, 2H), 1.93 (m, 2H), 1.66 (m,2H), 0.94 (t, 3H).

Intermediate 99:4-[5-(2-Chloro-pyrimidin-4-yl)-thiophen-2-ylmethyl]-piperazine-1-carboxylicacid tert-butyl ester was made from 97 by procedure B. LC-MS showed theproduct had the expected M+H⁺ of 395.

Compound 177:(S)-2-Chloro-4-(2-{4-[5-(2(S)-methyl-piperazin-1-ylmethyl)-thiophen-2-yl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 99 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M-Fir of 445. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.12 (d, 1H), 7.98 (d, 1H), 7.30 (s, 1H), 7.26 (d, 1H), 7.18 (d,1H), 7.02 (d, 1H), 6.80 (d, 1H), 4.28 (d, 1H), 3.78 (d, 1H), 3.68 (s,2H), 3.29 (m, 3H), 3.16 (m, 2H), 2.84 (m, 3H), 2.50 (m, 1H), 1.28 (t,3H).

Compound 178:4-[2-(4-{3-[(Ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-2-methyl-phenol:Intermediate 84 was coupled with 4-(2-amino-ethyl)-2-methyl-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M-Fir of 446. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.30 (s, 2H), 7.68 (m, 2H), 7.32 (d, 1H), 7.19 (m, 1H), 6.98 (s,1H), 6.89 (d, 1H), 6.63 (d, 1H), 4.53 (s, 2H), 3.78 (m, 2H), 3.60 (m,3H), 3.08 (m, 4H), 2.84 (t, 2H), 2.41 (d, 2H), 2.17 (m, 2H), 2.10 (s,3H), 1.32 (t, 3H).

Intermediate 100:4-{[5-(2-Chloro-pyrimidin-4-yl)-thiophen-2-ylmethyl]-ethyl-amino}-piperidine-1-carboxylicacid tert-butyl ester was made from 97 by procedure E. LC-MS showed theproduct had the expected M+H⁺ of 437.

Compound 179:2-Chloro-4-[2-(4-{5-[(ethyl-piperidin-4-yl-amino)-methyl]-thiophen-2-yl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 100 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 473. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.19 (d, 1H), 7.95 (d, 1H), 7.38 (d, 1H), 7.21 (d, 2H), 7.02 (d,1H), 6.80 (d, 1H), 4.54 (s, 2H), 3.68 (s, 2H), 3.54 (m, 3H), 3.06 (m,4H), 2.85 (t, 2H), 2.34 (d, 2H), 1.98 (m, 2H), 1.30 (t, 3H).

Intermediate 101:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-isopropyl-piperazine-1-carboxylicacid tert-butyl ester was made by procedure B from intermediate 1 and3-Isopropyl-piperazine-1-carboxylic acid tert-butyl ester. LC-MS showedthe product had the expected M+H⁺ of 431.

Compound 180:2-Chloro-4-(2-{4-[3-(2-isopropyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 101 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 467. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.28 (d, 2H), 8.19 (d, 1H), 7.74 (d, 1H), 7.61 (t, 1H), 7.47 (d,1H), 7.23 (s, 1H), 7.01 (d, 1H), 6.77 (d, 1H), 4.55 (d, 1H), 3.86 (s,2H), 3.70 (d, 1H), 3.49 (d, 1H), 3.38 (m, 1H), 3.14 (m, 3H), 2.89 (m,3H), 2.74 (t, 1H), 2.55 (m, 1H), 1.05 (t, 6H).

Intermediate 102: 3-(2-Chloro-5-fluoro-pyrimidin-4-yl)-benzaldehyde wasmade by procedure

A. LC-MS showed the product had the expected M+H⁺ of 237.

Intermediate 103:(3-{[3-(2-Chloro-5-fluoro-pyrimidin-4-yl)-benzyl]-methanesulfonyl-amino}-propyl)-carbamicacid tert-butyl ester was made from intermediate 102 by procedure Bfollowed by procedure D using methansulfonyl chloride. LC-MS showed theproduct had the expected M+H⁺ of 473.

Compound 181:N-(3-Amino-propyl)-N-(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 103 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 509. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.26 (d, 1H), 8.14 (s, 1H), 8.02 (d, 1H), 7.53 (m, 2H), 7.19 (d,1H), 7.01 (d, 1H), 6.80 (d, 1H), 4.50 (s, 2H), 3.59 (t, 2H), 3.38 (m,2H), 2.97 (s, 3H), 2.81 (t, 4H), 1.68 (m, 2H).

Compound 182:2-Methyl-4-(2-{4-[3-(2(S)-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 68 was coupled with 4-(2-amino-ethyl)-2-methyl-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 418. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.32 (s, 1H), 8.26 (d, 1H), 7.78 (d, 1H), 7.64 (t, 1H), 7.45 (d,1H), 7.13 (d, 1H), 6.98 (s, 1H), 6.88 (d, 1H), 6.60 (d, 1H), 4.71 (d,1H), 3.99 (d, 1H), 3.84 (s, 2H), 3.45 (m, 3H), 3.23 (m, 3H), 3.02 (t,1H), 2.86 (t, 2H), 2.07 (s, 3H), 1.54 (d, 3H).

Intermediate 104:3-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-azetidine-1-carboxylic acidtert-butyl ester: Intermediate 1 was coupled with3-Amino-azetidine-1-carboxylic acid tert-butyl ester following procedureB. LC-MS showed the product had the expected M+H⁺ of 375.

Intermediate 105:3-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-azetidine-1-carboxylicacid tert-butyl ester: Intermediate 104 was coupled with acetaldehydefollowing procedure E. LC-MS showed the product had the expected M+H⁺ of403.

Compound 183:4-[2-(4-{3-[(Azetidin-3-yl-ethyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 105 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 405. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.69 (s, 1H), 8.40 (d,1H), 8.34 (s, 1H), 7.96 (d, 1H), 7.72 (t, 1H), 7.68 (d, 1H), 7.11 (d,2H), 6.67 (d, 2H), 4.56 (m, 5H), 3.78 (m, 4H), 3.21 (q, 2H), 2.93 (t,2H), 1.39 (t, 3H).

Compound 184:4-(2-{4-[3-(2-Isopropyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 101 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 432. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.30 (s, 1H), 826 (d,1H), 8.20 (d, 1H), 7.74 (d, 1H), 7.60 (t, 1H), 7.47 (d, 1H), 7.08 (d,2H), 6.66 (d, 2H), 4.54 (d, 1H), 3.82 (m, 2H), 3.71 (d, 1H), 3.49 (d,1H), 3.33 (m, 1H), 3.14 (m, 3H), 2.98 (m, 1H), 2.89 (t, 2H), 2.76 (t,1H), 2.57 (m, 1H), 1.05 (t, 6H).

Compound 185:442-{4-[3-(2-Isopropyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 84 was coupled with 4-(2-Amino-ethyl)-naphthalen-1-olfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 483. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.22 (d, 1H), 8.07 (m, 2H), 7.78 (d, 1H), 7.57 (t, 1H), 7.46 (t,1H), 7.35 (t, 2H), 7.10 (m, 3H), 6.63 (d, 1H), 4.47 (s, 2H), 4.01 (s,2H), 3.75 (t, 1H), 3.58 (d, 2H), 3.46 (t, 2H), 3.24 (m, 2H), 3.10 (t,2H), 2.38 (d, 2H), 2.11 (m, 2H), 1.27 (t, 3H).

Intermediate 106:2-{2-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-ethyl}-pyrrolidine-1-carboxylicacid tert-butyl ester: 2-ethyl-pyrrolidine-1-carboxylic acid tert-butylester was coupled with intermediate 1 following procedure B. LC-MSshowed the product had the expected M+H⁺ of 417.

Intermediate 107:2-(2-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-ethyl)-pyrrolidine-1-carboxylicacid tert-butyl ester: Intermediate 106 was coupled with acetaldehydefollowing procedure E. LC-MS showed the product had the expected M+H⁺ of445.

Compound 186:4-{2-[4-(3-{[Ethyl-(2(S)-pyrrolidin-2-yl-ethyl)-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 107 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 447. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.62 (s, 1H), 8.37 (d,1H), 8.34 (m, 1H), 7.93 (d, 1H), 7.72 (t, 1H), 7.66 (d, 1H), 7.11 (d,2H), 6.67 (d, 2H), 4.52 (m, 2H), 3.95 (m, 2H), 3.58 (m, 2H), 3.27 (m,4H), 2.93 (t, 2H), 2.24 (m, 4H), 1.99 (m, 2H), 1.70 (m, 1H), 1.40 (t,3H).

Intermediate 108:2-Chloro-4-[3-(2-methyl-piperidin-1-ylmethyl)-phenyl]-pyrimidine:2-Methylpiperidine was coupled with intermediate 1 following procedureB. LC-MS showed the product had the expected M+H⁺ of 302.

Compound 187:2-Chloro-4-(2-{4-[3-(2(S)-methyl-piperidin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 108 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 438. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.29 (d, 1H), 8.24 (s, 1H), 8.00 (d, 1H), 7.61 (d, 1H), 7.44 (t,1H), 7.15 (s, 1H), 7.08 (d, 1H), 6.93 (d, 1H), 6.84 (d, 1H), 5.37 (t,1H), 4.36 (d, 1H), 3.75 (d, 1H), 3.66 (m, 2H), 2.93 (m, 2H), 2.80 (t,2H), 2.42 (s, 1H), 1.75 (m, 5H), 1.38 (m, 4H).

Intermediate 109:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-(1H-indol-3-ylmethyl)-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with2-(1H-Indol-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl esterfollowing procedure B. LC-MS showed the product had the expected M+H⁺ of518.

Compound 188:4-[2-(4-{3-[3(S)-(1H-Indol-3-ylmethyl)-piperazin-1-ylmethyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 109 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 520. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.51 (s, 1H), 8.29 (d,2H), 7.81 (d, 1H), 7.55 (m, 3H), 7.34 (d, 1H), 7.25 (s, 1H), 7.02 (m,4H), 6.69 (s, 2H), 4.54 (m, 2H), 4.08 (m, 1H), 3.90 (m, 2H), 3.61 (m,4H), 3.25 (m, 4H), 2.92 (t, 2H).

Intermediate 110:2-Benzyl-4-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with2-Benzyl-piperazine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 479.

Compound 189:4-(2-{4-[3-(3(R)-Benzyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 110 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 481. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.59 (s, 1H), 8.33 (d,2H), 7.90 (d, 1H), 7.67 (t, 1H), 7.61 (d, 1H), 7.28 (m, 5H), 7.11 d,2H), 6.68 (s, 2H), 4.64 (d, 2H), 4.16 (m, 1H), 3.91 (m, 2H), 3.56 (m,6H), 3.30 (m, 2H), 2.92 (t, 2H).

Compound 190:3-{2-[4-(3-{[Ethyl-(2(S)-pyrrolidin-2-yl-ethyl)-amino]-methyl}-phenyl)-pyrimidin-2-ylamino]-ethyl}-phenol:Intermediate 107 was coupled with 3-(2-Amino-ethyl)-phenol followingprocedure F. The resulting product was deprotected following procedureG2. LC-MS showed the product had the expected M+H⁺ of 447. ¹H NMR(Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm)δ 8.62 (s, 1H), 8.36 (d, 2H), 7.94 (d, 1H), 7.72 (t, 1H), 7.66 (d, 1H),7.05 (t, 1H), 6.78 (s, 2H), 6.59 (d, 1H), 4.53 (m, 2H), 3.90 (m, 2H),3.58 (m, 2H), 3.32 (m, 5H), 3.00 (t, 2H), 2.22 (m, 3H), 2.02 (m, 2H),1.71 (m, 1H), 1.40 (t, 3H).

Intermediate 111:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3-(R)Methyl-piperazine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 403.

Compound 191:[2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(2(R)-methyl-piperazin-1-ylmethyl)-phenyl}-pyrimidin-2-yl]-amine:Intermediate 111 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 425. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.72 (s, 1H), 8.36 (t, 2H), 7.97 (d, 1H), 7.73 (d, 1H), 7.69 (d,1H), 7.01 (d, 2H), 6.72 (s, 1H), 4.43 (d, 1H), 4.05 (m, 3H), 3.55 (m,6H), 3.39 (m, 1H), 3.06 (t, 2H), 1.77 (d, 3H).

Compound 192:N-(3-Amino-propyl)-N-(3-{5-fluoro-2-[2-(3-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 103 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 477. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.27 (d, 1H), 8.16 (s, 1H), 8.03 (d, 1H), 7.53 (m, 2H), 7.24 (m,1H), 7.07 (d, 1H), 7.00 (d, 1H), 6.87 (t, 1H), 4.50 (s, 2H), 3.65 (t,2H), 3.36 (t, 2H), 2.93 (m, 5H), 2.81 (t, 2H), 1.66 (m, 2H).

Intermediate 112:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-ethyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3-Ethyl-piperazine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 417.

Compound 193:[2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(2(S)-ethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 112 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The enantiomers of this product were separated bychiral HPLC, with compound 195 coming from the first peak to elute. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 439. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.74 (s, 1H), 8.38 (d,2H), 7.97 (d, 1H), 7.71 (m, 2H), 7.00 (d, 2H), 6.74 (s, 1H), 4.58 (m,6H), 4.07 (m, 4H), 3.25 (m, 3H), 3.07 (t, 2H), 1.39 (t, 3H).

Compound 194:N-(3-Amino-propyl)-N-(3-{5-fluoro-2-[2-(3-fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 113 was coupled with phenethylamine following procedure F.The resulting product was deprotected following procedure G2. LC-MSshowed the product had the expected M+H⁺ of 477. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.27 (d, 1H),8.15 (s, 1H), 8.03 (d, 1H), 7.55 (m, 2H), 7.26 (m, 4H), 7.17 (m, 1H),4.50 (s, 2H), 3.63 (t, 2H), 3.34 (m, 2H), 3.08 (m, 1H), 2.91 (m, 4H),2.79 (t, 2H), 1.65 (m, 2H).

Compound 195: The second peak to elute in the synthesis of compound 193,above, was isolated and deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 439. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.74 (s, 1H), 8.38 (d,2H), 7.97 (d, 1H), 7.71 (m, 2H), 7.00 (d, 2H), 6.74 (s, 1H), 4.58 (m,6H), 4.07 (m, 4H), 3.25 (m, 3H), 3.07 (t, 2H), 1.39 (t, 3H).

Intermediate 113:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-isobutyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with2-Isobutyl-piperazine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 445.

Compound 196: 4-(2-{4-[3-(3(S)-Isobutyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 113 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 447. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.65 (s, 1H), 8.36 (d,1H), 8.32 (s, 1H), 7.95 (d, 1H), 7.71 (t, 1H), 7.65 (d, 1H), 7.11 (d,1H), 6.68 (s, 1H), 4.70 (d, 1H), 4.57 (d, 1H), 3.96 (m, 2H), 3.81 (m,2H), 3.58 (m, 4H), 3.40 (t, 1H), 2.92 (t, 2H), 1.75 (m, 1H), 1.62 (t,2H), 1.00 (d, 3H), 0.98 (d, 3H).

Compound 197:[2-(3-Fluoro-phenyl)-ethyl]-{4-[3-(2-piperidin-4-yl-ethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 92 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 406. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.27 (d, 1H), 8.04 (s, 1H), 7.96 (m, 1H), 7.47 (d, 2H), 7.25 (m,2H), 7.09 (d, 1H), 7.04 (d, 1H), 6.89 (t, 1H), 3.80 (m, 2H), 3.36 (m,2H), 2.91 (m, 4H), 2.77 (t, 2H), 2.00 (d, 2H), 1.67 (m, 3H), 1.36 (m,2H).

Intermediate 114:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3,5-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 417.

Compound 198:[2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(2(S),6(R)-dimethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 114 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 439. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.57 (s, 1H), 8.36 (t, 2H), 7.94 (d, 1H), 7.74 (m, 2H), 6.99 (d,2H), 6.75 (t, 1H), 3.77 (m, 5H), 3.64 (m, 5H), 3.07 (t, 2H), 1.69 (d,6H).

Compound 199:N-(3-Amino-propyl)-N-(3-{2-[2-(3-chloro-phenyl)-ethylamino]-5-fluoro-pyrimidin-4-yl}-benzyl)-methanesulfonamide:Intermediate 113 was coupled with 2-(3-chloro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 493. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.27 (d, 1H), 8.15 (s, 1H), 8.02 (d, 1H), 7.53 (m, 2H), 7.17 (m,4H), 4.51 (s, 2H), 3.64 (t, 2H), 3.38 (t, 2H), 2.97 (m, 5H), 2.81 (t,2H), 1.66 (m, 2H).

Intermediate 115: 2-(3,5-Difluoro-phenyl)-2,2 dideutero-ethyl amine:(3,5-Difluoro-phenyl)-acetonitrile (10 g) was refluxed in THF (200 mL)containing 20% D₂0 and 10 g K₂CO₃ for 30 minutes. The solvent wasremoved and the process repeated. NMR showed complete exchange ofhydrogen for deuterium in the benzylic position. The resultingdeuterated nitrile was reduced to the phenethylamine as follows: Thenitrile was dissolved in THF (200 mL) and sodium borohydride (5 eq) andtrifluoroacetic acid (15 eq.). The mixture was heated to reflux for 5hours. After cooling, the reaction was quenched with methanol. Thesolvent was removed by rotary evaporation and the residue partitionedbetween ethyl acetate and sat. Sodium bicarbonate. Removal of thesolvent gave the expected product. LC-MS showed a single peak with theexpected M+H⁺ of 160.

Compound 200: [2-(3,5-Difluoro-phenyl)-2,2dideuteroethyl]-{4-[3-(2(S)-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 66 was coupled with 2-(3,5-difluoro-phenyl)-2,2dideutero-ethylamine following procedure F. The resulting product wasdeprotected following procedure G2. LC-MS showed the product had theexpected M+H⁺ of 427. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.3 ppm) δ 8.68 (s, 1H), 8.35 (d, 2H), 7.91 (d, 1H),7.71 (t, 1H), 7.67 (d, 1H), 6.98 (d, 2H), 6.74 (m, 1H), 4.29 (m, 1H),3.85 (m, 3H), 3.57 (m, 5H), 3.40 (m, 2H), 1.72 (d, 3H).

Compound 201:(4-{3-[(Azetidin-3-yl-ethyl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-[2-(3,5-difluoro-phenyl)-ethyl]-amine:Intermediate 114 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 425. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.74 (s, 1H), 8.38 (d, 2H), 7.97 (d, 1H), 7.71 (m, 2H), 7.90 (d,2H), 6.74 (s, 1H), 4.58 (m, 5H), 4.07 (m, 4H), 3.25 (q, 2H), 3.07 (t,2H), 1.39 (t, 3H).

Compound 202:[2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(2-isopropyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 101 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 452. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.31 (d, 1H), 8.27 (s, 1H), 8.18 (d, 1H), 7.72 (d, 1H), 7.59 (t,1H), 7.48 (d, 1H), 6.92 (d, 2H), 6.72 (t, 1H), 4.47 (d, 1H), 3.91 (s,2H), 3.59 (d, 1H), 3.44 (d, 1H), 3.33 (m, 1H), 3.02 (m, 5H), 2.81 (m,1H), 2.63 (t, 1H), 2.51 (m, 1H), 1.06 (t, 6H).

Compound 203:4-(2-{4-[3-(2(S)-Methyl-piperidin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 108 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 404. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.26 (d, 1H), 7.93 (s,1H), 7.86 (d, 1H), 7.36 (m, 2H), 6.99 (d, 2H), 6.92 (d, 1H), 6.63 (d,2H), 5.26 (t, 1H), 4.05 (d, 1H), 3.70 (d, 2H), 3.28 (d, 1H), 2.75 (m,4H), 2.37 (s, 1H), 1.63 (m, 2H), 1.39 (m, 3H), 1.20 (m, 4H).

Compound 204:(4-{3-[(Ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine:Intermediate 84 was coupled with 2-(3-trifluoromethyl-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 485. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.24 (m, 3H), 7.77 (t, 1H), 7.67 (t, 1H), 7.55 (m, 2H), 7.35 (m,3H), 4.54 (s, 2H), 3.79 (m, 4H), 3.60 (d, 2H), 3.08 (m, 5H), 2.42 (d,2H), 2.12 (m, 2H), 1.30 (t, 3H).

Compound 205:(4-{3-[(Ethyl-piperidin-3(S)-ylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-(2-thiophen-2-yl-ethyl)-amine:Intermediate 105 was coupled with 2-thiophen-2-yl-ethylamine followingprocedure F. The resulting product was deprotected following procedureG2. LC-MS showed the product had the expected M+H⁺ of 437. ¹H NMR(Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm)δ 8.71 (s, 1H), 8.40 (d, 2H), 7.98 (d, 1H), 7.75 (s, 2H), 7.21 (d, 1H),6.93 (d, 2H), 4.61 (s, 2H), 4.03 (s, 2H), 3.13 (m, 6H), 2.85 (t, 2H),2.67 (t, 1H), 2.39 (m, 2H), 1.81 (m, 4H), 1.29 (t, 3H).

Compound 206:[2-(3-Chloro-phenyl)-ethyl]-{5-fluoro-4-[3-(2-piperidin-4-yl-ethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 79 was coupled with 2-(3-chloro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 440. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.24 (d, 1H), 7.86 (d, 2H), 7.37 (m, 2H), 7.18 (m, 4H), 3.63 (t,2H), 3.32 (d, 2H), 3.91 (m, 4H), 2.76 (t, 2H), 1.99 (d, 2H), 1.67 (m,3H), 1.36 (m, 2H).

Compound 207:[2-(3-Fluoro-phenyl)-ethyl]-{5-fluoro-4-[3-(2-piperidin-4-yl-ethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 79 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 424. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.25 (d, 1H), 7.86 (d, 2H), 7.37 (m, 2H), 7.25 (q, 1H), 7.00 (m,2H), 6.88 (t, 1H), 3.64 (t, 2H), 3.35 (d, 2H), 2.91 (m, 4H), 2.76 (t,2H), 1.99 (d, 2H), 1.63 (m, 3H), 1.35 (m, 2H).

Compound 208:[2-(3,5-Difluoro-phenyl)-ethyl]-(4-{3-[3(S)-(1H-indol-3-ylmethyl)-piperazin-1-ylmethyl]-phenyl}-pyrimidin-2-yl)-amine:Intermediate 109 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 540. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.59 (s, 1H), 8.34 (d, 1H), 8.29 (d, 1H), 7.84 (d, 1H), 7.60 (m,3H), 7.33 (d, 1H), 7.26 (s, 1H), 6.98 (m, 4H), 6.72 (s, 1H), 4.63 (s,2H), 4.16 (m, 1H), 4.04 (s, 2H), 3.49 (m, 4H), 3.26 (m, 4H), 3.05 (t,2H).

Compound 209:{5-Fluoro-4-[3-(2-piperidin-4-yl-ethyl)-phenyl]-pyrimidin-2-yl}-phenethyl-amine:Intermediate 79 was coupled with phenethylamine following procedure F.The resulting product was deprotected following procedure G2. LC-MSshowed the product had the expected M+H⁺ of 406. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H),7.91 (s, 1H), 7.87 (d, 1H), 7.37 (m, 2H), 7.27 (m, 4H), 7.15 (m, 1H),3.62 (t, 2H), 3.34 (d, 2H), 2.91 (m, 4H), 2.76 (t, 2H), 1.99 (d, 2H),1.62 (m, 3H), 1.34 (m, 2H).

Compound 210:(4-{3-[(Azetidin-3-yl-ethyl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-[2-(3-fluoro-phenyl)-ethyl]-amine:Intermediate 104 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 407. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.72 (s, 1H), 8.36 (m, 2H), 7.97 (d, 1H), 7.70 (m, 2H), 7.27 (d,1H), 7.13 (d, 2H), 6.90 (s, 1H), 4.58 (m, 5H), 3.96 (m, 4H), 3.22 (q,2H), 3.06 (t, 2H), 1.38 (t, 3H).

Compound 211:[2-(3-Fluoro-phenyl)-ethyl]-{4-[3-(2-isopropyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 101 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 435. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.30 (d, 1H), 8.29 (s, 1H), 8.19 (d, 1H), 7.73 (d, 1H), 7.60 (t,1H), 7.49 (d, 1H), 7.24 (q, 1H), 7.05 (m, 2H), 6.87 (t, 1H), 4.51 (d,1H), 3.90 (s, 2H), 3.65 (d, 1H), 3.47 (d, 1H), 3.35 (m, 1H), 3.11 (m,3H), 3.02 (t, 2H), 2.90 (m, 1H), 2.71 (t, 1H), 2.52 (m, 1H), 1.05 (t,6H).

Compound 212:(4-{3-[(Ethyl-piperidin-3(S)-ylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-[2-(3-fluoro-phenyl)-ethyl]-amine:Intermediate 95 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 449. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.71 (s, 1H), 8.36 (t, 2H), 7.96 (d, 1H), 7.70 (m, 2H), 7.30 (s,1H), 7.12 (d, 2H), 6.91 (s, 1H), 4.60 (s, 2H), 3.99 (s, 2H), 3.06 (m,6H), 2.84 (m, 2H), 2.65 (t, 1H), 2.34 (m, 2H), 1.87 (m, 4H), 1.45 (t,3H).

Compound 213:{4-[3-(2-Isopropyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-(2-pyridin-4-yl-ethyl)-amine:Intermediate 101 was coupled with 2-pyridin-4-yl-ethylamine followingprocedure F. The resulting product was deprotected following procedureG2. LC-MS showed the product had the expected M+H⁺ of 417. ¹H NMR(Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm)δ 8.70 (d, 2H), 8.34 (d, 1H), 8.20 (s, 1H), 8.15 (d, 1H), 8.02 (d, 2H),7.68 (d, 1H), 7.56 (t, 1H), 7.40 (d, 1H), 4.47 (d, 1H), 4.03 (s, 1H),3.59 (d, 1H), 3.45 (d, 1H), 3.34 (t, 2H), 3.09 (m, 4H), 2.85 (m, 1H),2.65 (t, 1H), 2.52 (m, 1H), 1.07 (d, 3H), 1.05 (d, 3H).

Compound 214:[2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(2-ethyl-4-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Compound 193 was coupled with formaldehyde following procedure E. LC-MSshowed the product had the expected M+H⁺ of 452. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.68 (s, 1H),8.36 (d, 2H), 7.92 (d, 1H), 7.67 (m, 2H), 6.99 (d, 2H), 6.72 (s, 1H),5.07 (d, 1H), 4.36 (s, 1H), 3.43 (m, 7H), 3.04 (m, 4H), 2.36 (s, 1H),2.05 (m, 1H), 2.00 (s, 3H), 1.15 (t, 3H).

Intermediate 116: (2R)-tert-butyl4-(3-(2-chloropyrimidin-4-yl)benzyl)-2-phenylpiperazine-1-carboxylate:Intermediate 1 was coupled with 2-phenyl-piperazine-1-carboxylic acidtert-butyl ester following procedure B. LC-MS showed the product had theexpected M+H⁺ of 465.

Compound 215:4-(2-{4-[3-(3(R)-Phenyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 116 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 467. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.66 (s, 1H), 8.34 (d, 1H), 8.32 (s, 1H), 7.96 (d, 1H), 7.62 (m,4H), 7.53 (m, 3H), 7.10 (d, 2H), 6.67 (s, 2H), 5.04 (d, 1H), 4.66 (m,2H), 3.71 (m, 8H), 2.91 (t, 2H).

Compound 216:[2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(4-ethyl-2(S)-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Compound 154 was coupled with formaldehyde following procedure E. LC-MSshowed the product had the expected M+H⁺ of 453. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.33 (d, 1H),8.30 (s, 1H), 7.93 (s, 2H), 7.41 (m, 2H), 6.97 (d, 1H), 6.76 (d, 1H),6.62 (m, 1H), 5.44 (s, 1H), 4.20 (d, 1H), 3.72 (q, 2H), 3.19 (m, 3H),2.81 (m, 6H), 2.41 (m, 4H), 1.28 (t, 3H), 1.24 (d, 2H).

Intermediate 117: tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-amine:3-(2-Chloro-pyrimidin-4-yl)-benzaldehyde (intermediate 1) and tertbutylamine were coupled by procedure B. The yield was 97%. LC-MS showedthe product had the expected M+H⁺ of 276. ¹H NMR (Varian 300 MHz, CDCl₃,shifts relative to the solvent peak at 7.24 ppm) 8.6 (d, 1H) 8.1 (s, 1H)7.9 (d, 1H) 7.6 (d, 1H) 7.5 (m, 2H) 1.2 (s, 9H).

Intermediate 118: (Alloc protection)tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-carbamic acid allylester: tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-amine from theabove reaction (1.33 g, 4.84 mmol) was treated with allyl chloroformate(0.77 mL) in methylene chloride (15 mL) with diisopropyl ethylamine (1.7mL) at room temperature for 3 hours. The mixture was diluted withmethylene chloride (50 mL), washed with water (2×), brine, dried overNa₂SO₄, filtered. Removal of the solvent followed by chromatography onsilica gel (1:4 ethyl acetate:hexane eluent) afforded product in 61%yield. LC-MS showed the product had the expected M+H⁺ of 360. ¹H NMR(Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm)8.6 (d, 1H) 7.9 (d, 2H) 7.6 (d, 1H) 7.4 (m, 2H) 5.9 (m, 1H) 5.2 (m, 2H)4.7 (s, 2H) 4.6 (d, 2H) 1.4 (s, 9H).

Intermediate 119:tert-Butyl-(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}benzyl)-carbamicacid allyl ester:tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-carbamic acid allylester from the above reaction was coupled with tyramine followingprocedure F to give the title product in 91% yield. LC-MS showed theproduct had the expected M+H⁺ of 461. ¹H NMR (Varian 300 MHz, CDCl₃,shifts relative to the solvent peak at 7.24 ppm) 8.3 (d, 1H)) 7.9 (m,2H) 7.4 (m, 1H) 7.3 (m, 1H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.9 (m,1H) 5.3 (m, 2H) 5.1 (m, 2H) 4.7 (s, 2H) 4.6 (d, 2H) 3.7 (m, 2H) 2.9 (m,2H) 1.41 (s, 9H).

Intermediate 120:tert-Butyl-(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]pyrimidin-4-yl}-benzyl)-carbamicacid allyl ester:tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-carbamic acid allylester was coupled with 4-(2-amino-ethyl)-2-chloro-phenol hydrobromidesalt (intermediate 71) following procedure F to give the title productin 79% yield. LC-MS showed the product had the expected M+H⁺ of 495. ¹HNMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24ppm) 8.3 (d, 1H)) 7.9 (m, 2H) 7.4 (m, 1H) 7.3 (m, 1H) 7.2 (s, 1H) 7.0(d, 1H) 6.9 (m, 2H) 5.9 (m, 1H) 5.2 (m, 2H) 5.1 (m, 2H) 4.7 (s, 2H) 4.6(d, 2H) 3.7 (m, 2H) 2.9 (m, 2H) 1.41 (s, 9H).

Compound 217:4-(2-{4-[3-(tert-Butylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:tert-Butyl-(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}benzyl)-carbamicacid allyl ester (intermediate 118, 176 mg) was dissolved in methylenechloride (5 mL), followed by addition of diisopropylethylamine (0.11mL), 1,3-dimethylbarbituric acid (78 mg) then Pd(PPh₃)₄ (50 mg). Themixture was stirred at room temperature overnight. The mixture waswashed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered andchromatographed on silica gel with methylene chloride:methanol (95:5) toafford 112 mg of product in 78% yield. LC-MS showed the product had theexpected M+H⁺ of 377. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 1H) 7.5(m, 2H) 7.1 (m, 3H) 6.7 (m, 2H) 3.8 (s, 2H) 3.6 (m, 2H) 2.8 (m, 2H) 1.2(s, 9H).

Compound 218:4-(2-{4-[3-(tert-Butylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-2-chloro-phenol:tert-Butyl-(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]pyrimidin-4-yl}-benzyl)-carbamicacid allyl ester (Intermediate 120, 168 mg) was dissolved in methylenechloride (5 mL), followed by addition of diisopropylethylamine (0.11mL), 1,3-dimethylbarbituric acid (78 mg) then Pd(PPh₃)₄ (50 mg). Themixture was stirred at room temperature overnight. The mixture waswashed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered andchromatographed on silica gel with methyl chloride:methanol (95:5) toafford 120 mg of product in 86% yield. LC-MS showed the product had theexpected M+H⁺ of 411. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 1H) 7.5(m, 2H) 7.2 (d, 1H) 7.1 (d, 1H) 7.0 (m, 1H) 6.8 (d, 1H) 3.9 (s, 2H) 3.7(m, 2H) 2.8 (m, 2H) 1.3 (s, 9H).

Intermediate 121: 4-Aminomethyl-2-chloro-phenol hydrobromide salt: To asolution of 4-methoxybenzylamine (13.7 g) in acetic acid (150 mL) at 0°C. was dropwise added sulfuryl chloride (18.9 g). The suspension wasstirred at 10°-20° C. for 4 hours. Ether (300 mL) was added and thesolid was collected by filtration and washed with ether to afforded 16.9g of white solid intermediate upon dried under vacuum overnight. Theintermediate (11.43 g) was heated at 133° C. in 48% aqueous HBr (80 mL)for 4 hours then cooled with ice bath. The resulted solid was collectedby filtration, washed with methanol (8 mL) then ethyl acetate (20 mL) togive 12.16 g of the title product. LC-MS showed the product had theexpected M+H⁺ of 158. ¹H NMR (Varian 300 MHz, DMSO-d6, shifts relativeto the solvent peak at 2.49 ppm) δ 8.2 (s, br, 2H) 7.5 (s, 1H) 7.52 (m,1H) 7.0 (d, 1H) 3.9 (s, 2H) 3.3 (s, 1H).

Compound 219:2-Chloro-4-({4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-methyl)-phenol:[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-isopropyl-carbamic acid tert-butylester (intermediate 70) was coupled with 4-Aminomethyl-2-chloro-phenolhydrobromide salt (Intermediate 121) following procedure F thendeprotected by procedure G. LC-MS showed the product had the expectedM+H⁺ of 383. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative to thesolvent peak at 3.31 ppm) δ 8.5 (s, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.8 (d,1H) 7.7 (m, 1H) 7.6 (d, 1H) 7.4 (s, 1H) 7.2 (d, 1H) 6.9 (d, 1H) 4.3 (s,1H) 3.6 (m, 2H) 3.5 (m, 1H) 1.4 (d, 6H)

Intermediate 122: 2-(2H-Tetrazol-5-yl)-ethylamine HCl salt:3-Amino-propionitrile (14.0 g) was treated with (Boc)₂O (45.7 g) andNaHCO₃ (42.4 g) in tetrahydrofuran-water (120 mL/200 mL) at roomtemperature for 3 days. The organic layer was separated and aqueouslayer was extracted with ethyl acetate. The combined organic layer waswashed with water, brine and dried over Na₂SO₄, concentrated underreduced pressure. The residue was washed with 5% ethyl acetate in hexaneto give 18.65 g of solid intermediate in 55% yield. This intermediate(8.5 g) was treated with sodium azide (3.74 g) and NH₄Cl (3.1 g) in DMF(180 mL) at 90° C. for 4 days. The solvent was removed under reducedpressure and the residue was basified with 1 N NaOH, washed with ether(3×). The aqueous solution then was acidified with 1 N citric acid to pH3˜4, extracted with ethyl acetate (3×) and methylene chloride (3×). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give an oily product[2-(2H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (4.96 g) in35% yield. Deprotection of the material (2.72 g) with 6 N aqueous HCl(50 mL) at room temperature for 5 hours, followed by concentration andazeotroped with methanol in rotary evaporator gave the title product asa solid (1.80 g, 1:1 mixture with DMF). LC-MS showed the product had theexpected M+H⁺ of 114. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.31 ppm) δ 8.1 (s, 1H) 3.4 (d, 2H) 3.3 (m, 2H) 3.0(s, 3H) 2.9 (s, 3H).

Compound 220:{4-[3-(2-S-Methyl-piperazin-1-ylmethyl)-phenyl]pyrimidin-2-yl}-[2-(2H-tetrazol-5-yl)-ethyl]-amine:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester (intermediate 68) was coupled with2-(2H-tetrazol-5-yl)-ethylamine HCl salt (Intermediate 122) followingprocedure F then deprotection by procedure G2. LC-MS showed the producthad the expected M+H⁺ of 380. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.31 ppm) δ 8.7 (s, 1H) 8.4 (s, 1H) 8.3(d, 1H) 7.9 (d, 1H) 7.7 (d, 2H) 5.1 (s, br, 1H) 4.4 (s, br, 1H) 4.2 (s,br, 2H) 3.9 (s, br, 1H) 3.6 (m, 5H) 3.4 (m, 3H) 1.8 (d, 3H).

Compound 221:[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-{4-[3-(2-S-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Following procedure F4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester (intermediate 68) was coupled with2-(3-Chloro-4-methoxy-phenyl)-ethylamine HCl salt prepared in aprocedure described in preparation of Intermediate 121. Deprotection byprocedure G2 gave the title product. LC-MS showed the product had theexpected M+H⁺ of 452. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.31 ppm) δ 8.6 (s, 1H) 8.3 (d, 2H) 7.9 (d, 1H) 7.7(m, 1H) 7.6 (m, 1H) 7.4 (s, 1H) 7.2 (d, 1H) 6.9 (s, 1H) 5.0 (s, br, 1H)4.3 (s, br, 1H) 4.0 (s, br, 1H) 3.7 (m, 6H) 3.6 (m, 3H) 3.4 (s, br, 2H)3.0 (m, 2H) 1.7 (d, 3H).

Intermediate 123: 4-(2-Amino-ethyl)-2-chloro-phenylamine 2HCl salt: To asolution of 2-(4-aminophenyl)ethylamine (6.81 g) in methylene chloride(160 mL) with diisopropylethylamine (10.4 mL) at 0° C. was added (Boc)₂O(8.72 g) over 10 min. The mixture was stirred at room temperatureovernight. The reaction was worked up by washing with water, saturatedNaHCO₃, brine and dried over Na₂SO₄. Removal of solvent afforded a solid(9.54 g). The Boc protected amine (2.35 g) was heated with aceticanhydride (10 mL) at 100° C. for 30 min, cooled to 0° C. Acetic acid (8mL) was added, followed by NaOCl solution (4% Cl₂, 9 mL) dropwise andthe mixture was stirred at room temperature overnight. Solvent wasremoved under reduced pressure and the residue was dissolved in ethylacetate (250 mL), washed with saturated NaHCO₃, water, brine, dried overNa₂SO₄, concentrated and chromatographed on silica gel (ethylacetate:hexane=1:9 to 3:7) to afford[2-(4-acetylamino-3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl esteras a solid (0.82 g), which was deprotected with 4N HCl-dioxane (10 mL)in methanol (10 mL) at room temperature for 5 hours to give a solidtitle product (0.64 g) upon solvent removal. LC-MS showed the producthad the expected M+H⁺ of 171. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.31 ppm) δ 7.5 (d, 1H) 7.4 (m, 2H) 3.2(m, 2H). 3.0 (m, 2H).

Compound 222:[2-(4-Amino-3-chloro-phenyl)-ethyl]-{4-[3-(2-S-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester (intermediate 68) was coupled with4-(2-amino-ethyl)-2-chloro-phenylamine 2HCl salt (Intermediate 123)following procedure F then deprotection by procedure G2. LC-MS showedthe product had the expected M+H⁺ of 437. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.31 ppm) δ 8.7 (s, 1H) 8.4 (m,2H) 7.9 (d, 1H) 7.7 (m, 3H) 7.4 (m, 2H) 5.0 (s, br, 1H) 4.4 (s, br, 1H)4.0 (m, 2H) 3.7 (m, 5H) 3.4 (m, 2H) 3.1 (s, br, 2H) 1.7 (d, 3H).

Compound 223:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-isopropyl-2-methyl-nicotinamide:2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol(compound 132) was coupled with 2-methyl-nicotinic acid followingprocedure D2. LC-MS showed the product had the expected M+H⁺ of 516. ¹HNMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24ppm) δ 8.7 (d, 1H)) 8.5 (m, 2H) 8.3 (d, 1H) 8.1 (s, 1H) 7.9 (m, 1H) 7.4(m, 3H) 7.3 (m, 1H) 7.2 (m, 1H) 6.9 (d, 1H) 5.5 (s, br, 1H) 3.9 (s, 2H)3.7 (m, 2H) 2.9 (m, 6H) 1.2 (d, 6H).

Compound 224:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-isopropyl-4-methyl-nicotinamide:2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol(compound 132) was coupled with 4-methyl-nicotinic acid followingprocedure D2. LC-MS showed the product had the expected M+H⁺ of 516. ¹HNMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24ppm) δ 9.3 (s, 1H)) 8.6 (s, 1H) 8.5 (s, 1H) 8.3 (d, 1H) 8.1 (s, 1H) 7.9(d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (m, 3H) 6.9 (d, 1H) 5.6 (s, br, 1H)3.9 (s, 2H) 3.7 (m, 2H) 3.0 (d, 1H) 2.9 (m, 2H) 2.7 (s, 3H) 1.2 (d, 6H).

Compound 225:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-isopropyl-5-methyl-nicotinamide:2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol(compound 132) was coupled with 5-methyl-nicotinic acid followingprocedure D2. LC-MS showed the product had the expected M+H⁺ of 516. ¹HNMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24ppm) δ 9.2 (s, 1H)) 8.7 (s, 1H) 8.4 (s, 1H) 8.3 (m, 2H) 8.1 (s, 1H) 7.9(d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 7.0 (d, 1H) 5.6 (s, br, 1H)3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 2.4 (s, 3H) 1.2 (d, 6H).

Compound 226:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-isopropyl-6-methyl-nicotinamide:2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol(compound 132) was coupled with 6-methyl-nicotinic acid followingprocedure D2. LC-MS showed the product had the expected M+H⁺ of 516. ¹HNMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24ppm) δ 9.3 (s, 1H)) 8.3 (m, 2H) 8.2 (s, 1H) 8.0 (d, 2H) 7.6 (d, 1H) 7.4(m, 2H) 7.3 (d, 1H) 7.2 (s, 1H) 7.0 (d, 1H) 5.4 (s, br, 1H) 3.9 (s, 2H)3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 2.7 (s, 3H) 1.3 (d, 6H).

Compound 227:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-isopropyl-isonicotinamide:2-Chloro-4-(2-{4-[3-isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol(compound 132) was coupled with isonicotinic acid following procedureD2. LC-MS showed the product had the expected M+H⁺ of 502. ¹H NMR(Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm)δ 8.9 (d, 2H)) 8.5 (s, 1H) 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 2H) 7.9 (m,1H) 7.5 (d, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.5 (s, br, 1H) 3.9(s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 1.2 (d, 6H).

Compound 228:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]pyrimidin-4-yl}-benzyl)-N-isopropyl-6-trifluoromethyl-nicotinamide:2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl}-pyrimidin-2-ylamino]-ethyl)-phenol(compound 132) was coupled with 6-trifluoromethyl-nicotinic acidfollowing procedure D2. LC-MS showed the product had the expected M+H⁺of 570. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solventpeak at 7.24 ppm) δ 9.5 (s, 1H)) 8.6 (d, 1H) 8.5 (s, 1H) 8.2 (d, 1H) 8.1(s, 1H) 7.9 (m, 2H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.7(s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 3.0 (m, 2H) 1.2 (d, 6H).

Compound 229:N-(3-{2-[2-(3-Chloro-4-hydroxy-phenyl)-ethylamino]pyrimidin-4-yl}-benzyl)-N-isopropyl-4-trifluoromethyl-nicotinamide:2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol(compound 132) was coupled with 4-trifluoromethyl-nicotinic acidfollowing procedure D2. LC-MS showed the product had the expected M+H⁺of 570. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solventpeak at 7.24 ppm) δ 9.4 (s, 1H)) 9.0 (d, 1H) 8.4 (s, 1H) 8.3 (d, 1H) 8.1(s, 1H) 7.9 (d, 1H) 7.7 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9(d, 1H) 5.7 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H)1.2 (d, 6H).

Compound 230:5-Bromo-N-(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-N-isopropyl-nicotinamide:2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol(compound 132) was coupled with 5-bromo-nicotinic acid followingprocedure D2. LC-MS showed the product had the expected M+H⁺ of 581. ¹HNMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24ppm) δ 9.3 (s, 1H), 8.9 (s, 1H) 8.6 (s, 1H) 8.4 (s, 1H) 8.2 (d, 1H) 8.1(s, 1H) 7.9 (d, 1H) 7.5 (m, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.8(s, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 1.2 (d, 6H).

Compound 231: 1-Methyl-piperidine-4-carboxylic acid(3-{2-[2-(3-chloro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-isopropyl-amide:2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol(compound 132) was coupled with 1-methyl-piperidine-4-carboxylic acidfollowing procedure D2. LC-MS showed the product had the expected M+H⁺of 522. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solventpeak at 7.24 ppm) δ 8.6 (s, 1H) 8.3 (m, 1H) 7.8 (m, 2H) 7.4 (m, 1H) 7.2(s, 1H) 6.9 (m, 3H) 5.0 (s, br, 1H) 4.8 (m, 1H) 4.5 (d, 2H) 4.2 (m, 1H)3.7 (m, 2H) 3.4 (s, 1H) 3.2 (m, 2H) 2.8 (m, 2H 2.5 (m, 5H) 2.0 (s, br,2H) 1.9 (s, br, 1H) 1.2 (d, 3H) 1.0 (d, 3H).

Intermediate 124: 2-(1H-Indol-5-yl)-ethylamine: 5-Formyl indole (14.5 g)was refluxed with NH4OAc (10.0 g) in nitromethane ((100 mL) for 3 hours.The mixture was cooled and evaporated under reduced pressure. Theresidue was recrystallized from isopropanol to give the first portion ofintermediate and the mother liquid was purified by chromatograph(EtOAc:hexane=1:4 to 2:3) to the second portion intermediate of5-(2-nitro-vinyl)-1H-indole (2.09 g combined, in 11% yield), which wastreated with NaBH4 (1.85 g) in methanol (150 mL) at room temperature for35 min then quenched with acetic acid (4 mL), concentrated and followedby chromatography purification (EtOAc:hexane=1:9) to afford5-(2-nitro-ethyl)-1H-indole (1.37 g) in 65% yield. This nitro compoundwas hydrogenated with Pd—C (10%) under atmosphere hydrogen in methanolovernight to afford 2-(1H-indol-5-yl)-ethylamine in 99% yield. LC-MSshowed the product had the expected M+H⁺ of 161.

Compound 232:[2-(1H-Indol-5-yl)-ethyl]-{4-[3-(2-S-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester (intermediate 68) was coupled with2-(1H-indol-5-yl)-ethylamine (Intermediate 124) following procedure Fthen deprotected following procedure G. LC-MS showed the product had theexpected M+H⁺ of 427. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.31 ppm) δ 8.6 (m, 1H). 8.3 (m, 2H). 7.9 (m, 1H).7.6 (m, 5H) 7.2 (m, 2H). 4.3 (m, 1H). 3.7 (m, 10H). 3.2 (m, 2H) 1.7 (d,3H).

Compound 233:(4-{3-[(Ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-[2-(1H-indol-5-yl)-ethyl]-amine:4-{[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-ethyl-amino}-piperidine-1-carboxylicacid tert-butyl ester (intermediate 84) was coupled with2-(1H-indol-5-yl)-ethylamine (intermediate 124) following procedure Fthen deprotected following procedure G. LC-MS showed the product had theexpected M+H⁺ of 455. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.31 ppm) δ 8.7 (m, 1H) 8.4 (m, 3H) 7.9 (m, 1H) 7.6(m, 4H) 7.4 (m, 1H) 7.2 (m, 1H) 4.4 (m, 1H) 3.9 (m, 2H) 3.7 (m, 7H) 3.2(m, 3H) 2.5 (m, 2H) 2.3 (m, 2H) 1.3 (m, 3H).

Intermediate 125: Methanesulfonic acid3-(2-chloro-pyrimidin-4-yl)-benzyl ester: To a suspension of3-(2-chloro-pyrimidin-4-yl)-benzaldehyde (intermediate 1, 4.36 g) andNaBH₄ (0.3 g) in THF (70 mL) at room temperature was dropwise addedmethanol (5 mL). The mixture was stirred for 20 min and quenched withconcentrated HCl (1 mL) with water bath cooling. Solvent was removed byrotary evaporation. The residue was dissolved in EtOAc, washed withsaturated NaHCO₃, brine and dried over Na₂SO₄. Removal of solvent gave4.15 g of solid alcohol intermediate in 91% yield. The alcoholintermediate (3.2 g) was treated with mathanesulfonic anhydride (3.05g), diisopropylethylamine (3.8 mL) and DMAP (0.18 g) in methylenechloride (50 mL) at room temperature for 2 hours. The mixture wasdiluted with methylene chloride (150 mL), washed with water, brine,dried over Na₂SO₄ and purified by chromatograph (EtOAc:hexane=1:4 to2:3) to give a solid product (3.5 g) in 81% yield. LC-MS showed theproduct had the expected M+H⁺ of 299. ¹H NMR (Varian 300 MHz, CDCl₃,shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (d, 1H) 8.1 (m,2H) 7.7 (d, 1H) 7.6 (m, 2H) 5.3 (s, 1H) 3.0 (s, 3H).

Intermediate 126: 2-(S)-Methyl-piperazine-1-carboxylic acid tert-butylester: To the solution of (S)-(+)-2-methyl-piperazine (2.0 g) inmethylene chloride (15 mL) at 0° C. was added benzylchloroformate (3.0mL) dropwise. The mixture was stirred at 0° C. for one hour then at roomtemperature for 2 hours, cooled to 0° C. Diisopropylethylamine (4.5 mL)was added and followed by (Boc)₂O (4.8 g). The mixture was stirred atroom temperature overnight then the solvent was removed by rotaryevaporation. The residue was dissolved in EtOAc, washed with water,brine, dried over Na₂SO₄, chromatographed on silica gel(EtOAc:hexane=1:9) to give an oily intermediate (4.2 g) in 62% yield.Hydrogenation with Pd—C(10%) in methanol gave the title product (2.17 g)in 87% yield. LC-MS showed the product had the expected M+H⁺ of 201. ¹HNMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24ppm) δ 4.2 (s, br, 1H) 3.8 (m, 1H) 3.0 (m, 4H) 2.7 (m, 2H) 1.4 (s, 9H)1.2 (d, 3H).

Intermediate 127: 2-(R)-Methyl-piperazine-1-carboxylic acid tert-butylester: To the solution of (R)-(−)-2-methyl-piperazine (1.68 g) inmethylene chloride (15 mL) at 0° C. was added benzylchloroformate (2.5mL) dropwise. The mixture was stirred at 0° C. for one hour then at roomtemperature for 2 hours, cooled to 0° C. Diisopropylethylamine (3.8 mL)was added and followed by (Boc)₂O (4.0 g). The mixture was stirred atroom temperature overnight then the solvent was removed by rotaryevaporation. The residue was dissolved in EtOAc, washed with water,brine, dried over Na₂SO₄, chromatographed on silica gel(EtOAc:hexane=1:9) to give an oily intermediate. Hydrogenation withPd—C(10%) in methanol gave the title product (3.03 g) in 85% yield overtwo steps. LC-MS showed the product had the expected. M+H⁺ of 201. ¹HNMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24ppm) δ 4.2 (m, 1H) 3.8 (m, 1H) 3.0 (m, 4H) 2.7 (m, 2H) 1.4 (s, 9H) 1.2(d, 3H).

Intermediate 128:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 125 Methanesulfonic acid3-(2-chloro-pyrimidin-4-yl)-benzyl ester (0.70 g) and Intermediate 1262-(S)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.61 g) withdiisopropylethylamine (0.70 mL) in ethylene glycol dimethyl ether (20mL) was refluxed for 3 hours, cooled to room temperature, evaporatedunder reduced pressure and the residue was dissolved in dichloromethane,washed with water (3×), brine, dried over dried over Na₂SO₄,chromatographed on silica gel (dichloromethane:methanol=98:2) to give0.60 g of oily product with yield 64%. LC-MS showed the product had theexpected M+H⁺ of 403. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative tothe solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.0 (s, 1H) 7.9 (d, 1H) 7.6(d, 1H) 7.5 (m, 2H) 4.2 (S, 1 h) 3.8 (d, 1H) 3.4 (m, 2H) 3.0 (m, 1H) 2.7(d, 1H). 2.6 (d, 1H) 2.1 (m, 2H) 1.5 (s, 9H) 1.2 (d, 3H).

Intermediate 129:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-(R)-methyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 125 Methanesulfonic acid3-(2-chloro-pyrimidin-4-yl)-benzyl ester (0.70 g) and Intermediate 1272-(R)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.61 g) withdiisopropylethylamine (0.70 mL) in ethylene glycol dimethyl ether (20mL) was refluxed for 3 hours, cooled to room temperature, evaporatedunder reduced pressure and the residue was dissolved in dichloromethane,washed with water (3×), brine, dried over dried over Na₂SO₄,chromatographed on silica gel (dichloromethane:methanol=98:2) to give0.50 g of oily product with yield 53%. LC-MS showed the product had theexpected M+H⁺ of 403. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative tothe solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.0 (s, 1H) 7.9 (d, 1H) 7.6(d, 1H) 7.5 (m, 2H) 4.2 (S, 1 h) 3.8 (d, 1H) 3.4 (m, 2H) 3.0 (m, 1H) 2.7(d, 1H), 2.6 (d, 1H) 2.1 (m, 2H) 1.4 (s, 9H) 1.2 (d, 3H).

Compound 234:442-{4-[3-(3-S-Methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 1284-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester was coupled with tyramine following procedure Fthen deprotected following procedure G. LC-MS showed the product had theexpected M+H⁺ of 404. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.30 ppm) δ 8.6 (s, 1H) 8.4 (m, 2H) 7.9 (s, 1H) 7.6(d, 2H) 7.1 (s, 2H) 6.7 (a, 2H) 4.6 (S, 2H) 3.9 (s, 2H) 3.6 (m, 7H) 2.9(s, 2H) 1.4 (s, 3H).

Compound 235:4-(2-{4-[3-(3-R-Methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 1294-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-(R)-methyl-piperazine-1-carboxylicacid tert-butyl ester was coupled with tyramine following procedure Fthen deprotected following procedure G. LC-MS showed the product had theexpected M+H⁺ of 404. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.30 ppm) δ 8.6 (s, 1H) 8.4 (m, 2H) 7.9 (s, 1H) 7.6(d, 2H) 7.1 (s, 2H) 6.7 (s, 2H) 4.6 (S, 2H) 3.9 (s, 2H) 3.6 (m, 7H) 2.9(s, 2H) 1.4 (s, 3H).

Compound 236:[2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(3-S-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 1304-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-(S)-methyl-piperazine-1-carboxylicacid tert-butyl ester was coupled with 2-(3,5-difluorophenyl)ethanaminefollowing procedure F then deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 424. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.7 (s, 1H)8.4 (d, 2H) 7.9 (d, 1H) 7.7 (m, 2H) 7.0 (d, 2H) 6.7, (m, 1H) 4.6 (S, 2H)4.0 (m, 2H) 3.7 (m, 7H) 3.1 (m, 2H) 1.4 (d, 3H).

Compound 237:[2-(3,5-Difluoro-phenyl)-ethyl]-{4-[3-(3-R-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 1314-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-(R)-methyl-piperazine-1-carboxylicacid tert-butyl ester was coupled with 2-(3,5-difluorophenyl)ethanaminefollowing procedure F then deprotected following procedure G. LC-MSshowed the product had the expected M+H⁺ of 424. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.6 (s, 1H)8.4 (m, 2H) 7.9 (s, 1H) 7.6 (d, 2H) 7.1 (s, 2H) 6.7 (s, 2H) 4.6 (S, 2H)3.9 (s, 2H) 3.6 (m, 7H) 2.9 (s, 2H) 1.4 (s, 3H).

Intermediate 130:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-ethyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3-ethyl-piperazine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 417.

Compound 238:4-(2-{4-[3-(2-Ethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 130 was coupled with tyramine following procedure F. Theproduct was deprotected following procedure G2. LC-MS showed the producthad the expected M+H⁺ of 418. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.3 ppm) δ 8.35 (s, 1H) 8.29 (d, 2H) 8.7.81 (d, 1H) 7.68 (t, 1H) 7.49 (d, 1H) 7.2-7.2 (m, 3H) 6.68 (d, 2H) 4.8(d, 1H) 4.17 (d, 1H) 3.85 (br s, 2H) 3.68 (d, 1H) 3.1-3.6 (m, 6H) 2.9(t, 2H) 2.2 (m, 1H) 1.9 (m, 1H) 1.1 (t, 3H).

Intermediate 131:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-propyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3-propyl-piperazine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 431.

Compound 239:4-(2-{4-[3-(2-Propyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 131 was coupled with tyramine following procedure F. Theproduct was deprotected following procedure G. LC-MS showed the producthad the expected M+H⁺ of 432. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.3 ppm) δ 8.35 (s, 1H) 8.29 (d, 2H) 8.7.81 (d, 1H) 7.68 (t, 1H) 7.49 (d, 1H) 7.2-7.2 (m, 3H) 6.68 (d, 2H) 4.8(d, 1H) 4.17 (d, 1H) 3.85 (br s, 2H) 3.68 (d, 1H) 3.1-3.6 (m, 6H) 2.9(t, 2H) 2.2 (m, 1H) 1.9 (m, 1H) 1.38-1.65 (m, 1H) 1.05 (t, 3H).

Compound 240:(4-{3-[(Ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-(2-thiophen-2-yl-ethyl)-amine:Intermediate 84 was coupled with 2-thiophen-2-yl-ethylamine followingprocedure F. The product was deprotected following procedure G2. LC-MSshowed the product had the expected M+H⁺ of 422.

Intermediate 132:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-piperazine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester: Intermediate 1 was coupled withpiperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esterfollowing procedure B. LC-MS showed the product had the expected M+H⁺ of447.

Compound 241:4-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-piperazine-2-carboxylicacid methyl ester: Intermediate 132 was coupled with tyramine followingprocedure F. The product was deprotected following procedure G2. LC-MSshowed the product had the expected M+H⁺ of 448.

Compound 242:[2-(3-Chloro-phenyl)-ethyl]-(4-{3-[(ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-amine:Intermediate 84 was coupled with 2-(3-chloro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 450. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.7 (s, 1H) 8.36 (d, 2H) 7.95 (d, 1H) 7.68-7.8 (m, 2H) 7.4 (s,1H) 7.25 (br s, 2H) 7.16 (s, 1H) 4.56 (br s, 2H) 3.88 (m, 3H) 3.62 (m,2H) 3.15 (m, 1H) 3.05 (m, 2H) 2.47 (m, 2H) 2.2 (m, 2H) 1.33 (t, 3H).

Compound 243: Intermediate 68 was coupled with2-thiophen-2-yl-ethylamine following procedure F. The resulting productwas deprotected following procedure G2. LC-MS showed the product had theexpected M+H⁺ of 394. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.30 ppm) δ 8.7 (s, 1H) 8.4 (d, 2H) 7.85 (s, 1H)7.72 (m, 2H) 7.22 (s, 1H) 6.95 (m, 2H) 4.75 (d, 1H) 4.02 (d, 1H) 3.9 (brs, 2H) 3.4-3.65 (m, 3H) 3.2-3.4 (m, 4H) 3.05 (m, 3H) 1.45 (d, 3H).

Compound 244: Intermediate 68 was coupled with 2,5difluorophenethylamine following procedure F. The resulting product wasdeprotected following procedure G. LC-MS showed the product had theexpected M+H⁺ of 424. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.30 ppm) δ 8.7 (s, 1H) 8.5 (d, 2H) 8.0 (d, 1H) 7.72(m, 2H) 7.22 (s, 1H) 6.9-7.05 (m, 2H) 4.75 (d, 1H) 4.02 (d, 1H) 3.9 (brs, 2H) 3.45-3.8 (m, 3H) 3.2-3.4 (m, 4H) 3.05 (m, 3H) 1.8 (d, 3H).

Intermediate 133: 3-(2-Fluoro-pyridin-4-yl)-benzaldehyde: 2fluoro-4-iodo pyridine (5 g), 3 formylphenylboronic acid (4 g), andpalladium tetrakis triphenylphosphine were suspended in 500 mL of THF.Potassium carbonate (7.42 g) was added along with 50 mL of water. Theflask was purged with nitrogen and the mixture heated to 65 C for 4hours. The solvent was removed by rotary evaporation and the residuepartitioned between ethyl acetate and water. Removal of the ethylacetate gave a residue which was chromatographed on silica gel (1:1ethyl acetate hexanes) to give the desired product. Yield: 1.42 g. LC-MSshowed the product had the expected M+H⁺ of 202.

Intermediate 134: (1.4 g) was dissolved in methylene chloride (30 mL)along with 0.78 g of 3-(S) Methyl-piperazine-1-carboxylic acidtert-butyl ester. Sodium triacetoxyborohydride (1.4 g) was added and themixture stirred at room temperature for 2 hours. The mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with a saturated solution of sodium chloride and the solventremoved. The residue was chromatographed on silica gel to give 1.14 g ofthe desired product. LC-MS showed the product had the expected M+H⁺ of386.

Compound 245:4-(2-{4-[3-(2-Methyl-piperazin-1-ylmethyl)-phenyl]-pyridin-2-ylamino}-ethyl)-phenol:134 (0.3 g) was dissolved in 4 mL of ethanol along with 300 mg oftyramine and 250 uL of diisopropylethylamine. The mixture was placed ina sealed tube and heated under microwave irradiation to 170 C for 12hours. The solvent was removed and the residue chromatographed on silicagel (1:1 ethyl acetate hexanes as eluent.) The resulting material wasfurther purified by reverse phase HPLC to give 23 mg of product. Thiswas deprotected following procedure G2. LC-MS showed the product had theexpected M+H⁺ of 403. ¹H NMR (Varian 300 MHz, CD₃OD, shifts relative tothe solvent peak at 3.30 ppm) δ 8.27 (m, 1H) 7.8-7.9 (m, 2H) 7.58-7.8(m, 4H) 7.28-7.38 (m, 2H) 7.25-7.35 (m, 2H) 7.15 (d, 2H) 6.7 (d, 1H)4.75 (d, 1H) 4.02 (d, 1H) 3.9 (br s, 2H) 3.45-3.8 (m, 3H) 3.2-3.4 (m,4H) 3.05 (m, 3H) 1.8 (d, 3H).

Compound 246:{4-[3-(2-Ethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-[2-(3-fluoro-phenyl)-ethyl]-amine:Intermediate 130 was coupled with 3-fluorophenethylamine followingprocedure F. The resulting product was deprotected following procedureG2. LC-MS showed the product had the expected M+H⁺ of 420. ¹H NMR(Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.30 ppm)δ 8.25-8.4 (m, 2H) 7.8 (d, 1H) 7.7 (t, 1H) 7.5 (d, 1H) 7.18-7.35 (m, 2H)7.05-7.15 (m, 2H) 6.9 (m, 1H) 4.72 (d, 1H) 4.1 (d, 1H) 3.92 (br s, 2H)3.65 (m, 1H) 3.3-3.5 (m, 6H) 3.12 (m, 1H) 3.05 (m, 2H) 2.18 (m, 1H) 1.92(m, 1H) 1.1 (t, 3H).

Compound 247:(4-{3-[(Ethyl-piperidin-4-yl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-(2-pyridin-4-yl-ethyl)-amine:Intermediate 84 was coupled with 2-Pyridin-4-yl-ethylamine followingprocedure F. The resulting product was deprotected following procedureG. LC-MS showed the product had the expected M+H⁺ of 417. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.72(d, 2H) 88.3-8.5 (m, 2H) 8.06 (d, 2H) 7.88 (d, 1H) 7.72 (m, 1H) 7.58 (d,1H) 4.59 (d, 2H) 4.12 (br s, 2H) 3.85 (m, 1H) 3.62 (m, 2H) 3.1-3.45 (m,6H) 2.48 (m, 2H) 2.18-2.24 (m, 2H) 1.35 (t, 3H).

Intermediate 135:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-[1,4]diazepane-1-carboxylic acidtert-butyl ester: Intermediate 1 was coupled with[1,4]Diazepane-1-carboxylic acid tert-butyl ester following procedure B.LC-MS showed the product had the expected M+H⁺ of 403.

Compound 248:[4-(3-[1,4]Diazepan-1-ylmethyl-phenyl)-pyrimidin-2-yl]-(2-thiophen-2-yl-ethyl)-amine:Intermediate 135 was coupled with 2-thiophen-2-yl-ethyl)-amine followingprocedure F. The resulting product was deprotected following procedureG2. LC-MS showed the product had the expected M+H⁺ of 394. ¹H NMR(Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.30 ppm)δ 8.38 (m, 3H) 7.85 (m, 1H) 7.71 (m, 1H) 7.53 (m, 1H) 7.1-7.3 (m, 2H)6.85-7.0 (m, 2H) 4.59 (br s, 2H) 3.95 (br s, 2H) 3.68-3.83 (m, 3H) 3.55(m, 2H) 3.45 (m, 2H) 3.2-3.45 (m, 3H).

Intermediate 136:4(R)-[3-(2-Chloro-pyrimidin-4-yl)-benzylamino]-3(S)-methyl-piperidine-1-carboxylicacid benzyl ester: Intermediate 1 was coupled with4(R)-amino-3(S)-methyl-piperidine-1-carboxylic acid benzyl ester(prepared according to literature procedure (ref 1)) following procedureB. LC-MS showed the product had the expected M+H⁺ of 451.

Compound 249:4-[2-(4-{3-[(3(S)-Methyl-piperidin-4(R)-ylamino)-methyl]-phenyl}-pyrimidin-2-ylamino)-ethyl]-phenol:Intermediate 136 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G3. LC-MS showedthe product had the expected M+H⁺ of 418. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.63 (s, 1H) 8.36 (d,2H) 7.95 (d, 1H) 7.75 (t, 1H) 7.67 (d, 1H) 7.15 (d, 2H) 6.71 (d, 2H)4.50 (s, 2H) 3.96 (m, 1H) 3.80 (m, 1H) 3.72 (m, 1H) 3.56 (d, 1H) 3.34(d, 1H) 3.20 (t, 2H) 2.96 (t, 2H) 2.80 (m, 1H) 2.38 (dd, 2H) 1.36 (d,3H).

Compound 250:[2-(3,5-Difluoro-phenyl)-ethyl]-(4-{3-[(3(S)-methyl-piperidin-4(R)-ylamino)-methyl]-phenyl}-pyrimidin-2-yl)-amine:Intermediate 136 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G3. LC-MS showed the product had the expected M+H⁺ of 418LC-MS showed the product had the expected M+H⁺ of 438. ¹H NMR (Varian300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.70(s, 1H) 8.39 (d, 2H) 7.97 (d, 1H)) 7.74 (d, 2H) 7.00 (d, 2H) 6.86 (d,1H) 4.57 (s, 2H) 4.06 (m, 1H) 3.88 (m, 1H) 3.72 (m, 1H) 3.57 (m, 1H)3.42 (d, 2H) 3.10 (t, 2H) 2.92 (m, 2H) 2.38 (m, 2H) 1.38 (d, 3H).

Compound 251:[2-(4-Bromo-phenyl)-ethyl]-(4-{3-[(3(S)-methyl-piperidin-4(R)-ylamino)-methyl]-phenyl}-pyrimidin-2-yl)-amine:Intermediate 136 was coupled with 2-(4-bromo-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G3. LC-MS showed the product had the expected M+H⁺ of 481. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.67 (s, 1H) 8.39 (d, 2H) 7.95 (d, 1H)) 7.69 (t, 1H) 7.40 (d, 2H)7.28 (d, 2H) 4.50 (s, 2H) 4.00 (m, 1H) 3.84 (m, 1H) 3.72 (m, 1H) 3.57(m, 1H) 3.42 (d, 1H) 3.36 (d, 1H) 3.20 (t, 2H) 3.04 (t, 2H) 2.30 (m, 2H)1.30 (d, 3H).

Intermediate 137:1-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-piperazine-2-carboxylic acid:Intermediate 1 was coupled with4-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-piperazine-1,3-dicarboxylic acid1-tert-butyl ester following procedure B. LC-MS showed the product hadthe expected M+H⁺ of 433.

Compound 252:1-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-piperazine-2-carboxylicacid: Intermediate 137 was coupled with tyramine following procedure F.The resulting product was deprotected following procedure G2. LC-MSshowed the product had the expected M+H⁺ of 434. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.47 (s, 1H)8.36 (d, 2H) 7.88 (d, 1H) 7.74 (t, 1H) 7.61 (d, 1H) 7.15 (d, 2H) 6.68(d, 2H) 4.68 (dd, 1H) 4.39 (s, 2H) 3.96 (t, 2H) 3.84 (dd, 2H) 3.52 (t,2H) 3.44 (t, 2H) 2.95 (t, 2H).

Compound 253:1-(3-{2-[2-(3,5-Difluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-piperazine-2-carboxylicacid: Intermediate 137 was coupled with2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resultingproduct was deprotected following procedure G2. LC-MS showed the producthad the expected M+H⁺ of 454. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.3 ppm) δ 8.47 (s, 1H) 8.36 (d, 1H))8.33 (d, 1H) 7.87 (d, 1H) 7.71 (t, 1H) 7.65 (d, 1H) 7.00 (d, 2H) 6.77(s, 1H) 4.63 (dd, 1H) 4.36 (s, 2H) 4.08 (t, 2H) 3.84 (dd, 2H) 3.65 (t,2H) 3.47 (t, 2H) 3.09 (t, 2H).

Intermediate 158:3-Carbamoyl-4-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 137 was converted to Intermediate138 following literature procedure (ref 2). LC-MS showed the product hadthe expected M+H⁺ of 432.

Compound 254:1-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-piperazine-2-carboxylicacid amide: Intermediate 138 was coupled with tyramine followingprocedure F. The resulting product was deprotected following procedureG2. LC-MS showed the product had the expected M+H⁺ of 433. ¹H NMR(Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3 ppm)δ 8.15 (s, 1H) 8.11 (d, 1H) 8.07 (d, 1H) 7.77 (d, 1H) 7.58 (t, 1H) 7.50(d, 1H) 7.15 (d, 2H) 6.70 (d, 2H) 4.00 (dd, 2H) 3.78 (dd, 1H) 3.65 (t,2H) 3.35 (dd, 2H) 3.07 (t, 2H) 2.96 (t, 2H) 2.87 (t, 2H).

Compound 255:1-(3-{2-[2-(3-Fluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-piperazine-2-carboxylicacid amide: Intermediate 138 was coupled with2-(3-fluoro-phenyl)-ethylamine following procedure F. The resultingproduct was deprotected following procedure G2. LC-MS showed the producthad the expected M+H⁺ of 435. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.3 ppm) δ 8.33 (d, 1H) 8.27 (s, 1H)8.19 (d, 1H) 7.75 (d, 1H) 7.58 (t, 1H) 7.54 (d, 1H)) 7.30 (m, 1H) 7.13(t, 2H) 6.92 (m, 1H) 3.98 (dd, 2H) 3.78 (dd, 1H) 3.40-3.60 (m, 6H) 3.24(d, 2H) 3.08 (t, 2H).

Compound 256:1-(3-{2-[2-(3,5-Difluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-piperazine-2-carboxylicacid amide: Intermediate 138 was coupled with2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resultingproduct was deprotected following procedure G2. LC-MS showed the producthad the expected M+H⁺ of 453. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.3 ppm) δ 8.44 (s, 1H) 8.38 (d, 1H)8.33 (d, 1H) 7.86 (d, 1H) 7.68 (t, 1H) 7.63 (d, 1H)) 6.99 (d, 2H) 6.75(m, 1H) 4.47 (d, 2H) 4.26 (dd, 1H) 4.22 (t, 2H) 3.80 (dd, 2H) 3.53 (t,2H) 3.47 (t, 2H) 3.10 (t, 2H).

Intermediate 139:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3-cyano-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3-cyano-piperazine-1-carboxylic acid tert-butyl ester (generatedaccording to literature procedure (ref 3)) following procedure B. LC-MSshowed the product had the expected M+H⁺ of 414.

Compound 257:1-(3-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-piperazine-2-carbonitrile:Intermediate 139 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺—CN of 388. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.32 (d, 1H)8.27 (s, 1H) 8.23 (d, 1H) 7.75 (d, 1H) 7.62 (t, 1H) 7.55 (d, 1H) 7.14(d, 2H) 6.71 (d, 2H) 4.38 (s, 2H) 3.92 (dd, 1H) 3.80 (d, 2H) 3.40 (t,2H) 3.24 (t, 2H) 2.95 (t, 2H) 2.84 (t, 2H).

Intermediate 140:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2-cyano-piperazine-1-carboxylicacid benzyl ester: Intermediate 1 was coupled with2-cyano-piperazine-1-carboxylic acid benzyl ester (generated accordingto literature procedure (ref 4)) following procedure B. LC-MS showed theproduct had the expected M+H⁺ of 448.

Compound 258:4-(3-{2-[2-(3,5-Difluoro-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-piperazine-2-carbonitrile:Intermediate 140 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G3. LC-MS showed the product had the expected M+H₃O⁺ of 453.¹H NMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at3.3 ppm) δ 8.37 (d, 1H) 8.19 (s, 1H) 8.15 (d, 1H) 7.68 (d, 1H) 7.60 (t,1H) 7.37 (d, 1H) 6.94 (d, 2H) 6.85 (m, 1H) 4.60 (s, 2H) 4.05 (dd, 1H)3.94 (t, 2H) 3.52 (dd, 2H) 3.24 (t, 2H) 3.03 (t, 2H) 2.58 (t, 2H).

Intermediate 141:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-3,3-dimethyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 417.

Compound 259:{4-[3-(2,2-Dimethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-[2-(3-fluoro-phenyl)-ethyl]-amine:Intermediate 141 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H₃O⁺ of 438.¹H NMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at3.3 ppm) δ 8.75 (s, 1H) 8.36 (d, 2H) 7.96 (d, 1H) 7.65 (m, 2H) 7.27 (m,1H) 7.18 (m, 2H)) 6.92 (m, 1H) 4.54 (s, 2H) 3.96 (t, 2H) 3.72 (s, 2H)3.59 (t, 2H) 3.35 (t, 2H) 3.08 (t, 2H) 1.74 (s, 6H).

Compound 260:[2-(3,5-Difluoro-phenyl)-ethyl]-{-4-[3-(2,2-dimethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 141 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H₃O⁺ of 456.¹H NMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at3.3 ppm) δ 8.76 (s, 1H) 8.36 (d, 1H) 8.33 (d, 1H) 7.97 (d, 1H) 7.70 (t,2H) 7.03 (d, 2H) 6.76 (m, 1H) 4.54 (s, 2H) 3.98 (t, 2H) 3.72 (s, 2H)3.35 (m, 4H) 3.10 (t, 2H) 1.74 (s, 6H).

Compound 261:442-{4-[3-(2,2-Dimethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 141 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H₃O⁺ of 436. ¹H NMR (Varian 300 MHz,CD₃OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.72 (s, 1H)8.34 (d, 2H) 7.95 (d, 1H) 7.68 (m, 2H) 7.17 (d, 2H) 6.72 (d, 2H) 4.54(s, 2H) 3.96 (t, 2H) 3.71 (s, 2H) 3.35 (m, 4H) 2.96 (t, 2H) 1.76 (s,6H).

Intermediate 142:4-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2,6-dimethyl-piperazine-1-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester followingprocedure B. LC-MS showed the product had the expected M+H⁺ of 417.

Compound 262:4-(2-{4-[3-(3,5-Dimethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 142 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 418. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.67 (s, 1H) 8.56 (d,1H)) 8.52 (d, 1H) 8.00 (d, 1H) 7.75 (t, 1H) 7.65 (d, 1H) 7.15 (d, 2H)6.67 (d, 2H) 4.70 (s, 2H) 3.75 (d, 2H) 3.70 (d, 2H) 3.60-3.66 (m, 2H)3.40 (t, 2H) 2.96 (t, 2H) 1.44 (d, 6H).

Compound 263:2-Chloro-4-(2-{4-[3-(3,5-dimethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 142 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 452. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.63 (s, 1H) 8.35 (d, 2H)) 7.93 (d, 1H) 7.74 (d, 1H) 7.62 (d, 1H)7.17 (s, 1H) 7.07 (d, 1H) 6.74 (d, 1H) 4.60 (s, 2H) 3.60-3.70 (m, 6H)3.35 (t, 2H) 2.92 (t, 2H) 1.44 (d, 6H).

Compound 264:[2-(3,5-Difluoro-phenyl)-ethyl]-{-4-[3-(3,5-dimethyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine:Intermediate 142 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 438. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.32 (s, 1H) 8.12 (d, 1H)) 7.98 (d, 1H) 7.47 (m, 2H) 7.12 (d, 1H)6.90 (d, 2H) 6.75 (d, 1H) 3.75 (t, 2H) 3.60 (m, 4H) 3.47 (t, 2H) 2.98(t, 2H) 2.90 (t, 2H) 1.04 (d, 6H).

Intermediate 143:5-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester: Intermediate 1 was coupled with2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterfollowing procedure B. LC-MS showed the product had the expected M+H⁺ of401.

Compound 265:2-Chloro-4-(2-{4-[3-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 143 was coupled with 4-(2-amino-ethyl)-2-chloro-phenolfollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 436. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.38 (s, 1H) 8.26 (d, 2H) 7.87 (d, 1H) 7.72 (m, 1H) 7.48 (d, 1H)7.20 (s, 1H) 7.00 (d, 1H) 6.79 (d, 1H) 4.62 (s, 2H) 3.92 (d, 2H) 3.74(d, 2H) 3.61 (t, 2H) 3.24 (t, 2H) 2.88 (t, 2H) 2.76 (d, 1H) 2.37 (d,1H).

Compound 266:4-(2-{4-[3-(2,5-Diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 142 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 402. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.43 (s, 1H) 8.37 (d,1H) 8.34 (d, 1H) 8.04 (d, 1H) 7.73 (t 1H) 7.65 (d, 1H) 7.17 (d, 2H) 6.69(d, 2H) 4.62 (s, 2H) 4.19 (d, 2H) 3.92 (d, 2H) 3.63 (t, 2H) 3.23 (d, 2H)2.94 (t, 2H) 2.61 (d, 1H) 2.37 (d, 1H).

Compound 267:{4-[3-(2,5-Diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenyl]-pyrimidin-2-yl}-[2-(3-fluoro-phenyl)-ethyl]-amine:Intermediate 142 was coupled with 2-(3-fluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 404. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.45 (s, 1H) 8.36 (d, 2H) 7.89 (d, 1H) 7.73 (t, 1H) 7.54 (d, 1H)7.27 (q, 1H) 7.10 (m, 2H) 6.91 (t, 1H) 4.63 (q, 2H) 4.61 (d, 2H) 3.92(m, 3H) 3.78 (d, 1H) 3.59 (t, 2H) 3.07 (t, 2H) 2.76 (d, 1H) 2.33 (d,1H).

Compound 268:{4-[3-(2,5-Diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenyl]-pyrimidin-2-yl}-[2-(3,5-difluoro-phenyl)-ethyl]-amine:Intermediate 142 was coupled with 2-(3,5-difluoro-phenyl)-ethylaminefollowing procedure F. The resulting product was deprotected followingprocedure G2. LC-MS showed the product had the expected M+H⁺ of 422. ¹HNMR (Varian 300 MHz, CD₃OD, shifts relative to the solvent peak at 3.3ppm) δ 8.78 (s, 1H) 8.38 (d, 2H) 8.00 (d, 1H) 7.77 (t, 1H) 7.68 (d, 1H)7.00 (d, 2H) 6.75 (t, 1H) 4.84 (d, 1H) 4.65 (s, 2H) 4.60 (d, 1H) 4.24(d, 1H) 4.10 (d, 1H) 3.89 (d, 1H) 3.68 (d, 1H) 3.63 (t, 2H) 3.07 (t, 2H)2.86 (d, 1H) 2.37 (d, 1H).

Compound 269:{4-[3-(2,5-Diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenyl]-pyrimidin-2-yl}-[2,2,2-(dideutero-3,5-difluoro-phenyl)-ethyl]-amine:Intermediate 142 was coupled 115 following procedure F. The resultingproduct was deprotected following procedure G2. LC-MS showed the producthad the expected M+H⁺ of 424. ¹H NMR (Varian 300 MHz, CD₃OD, shiftsrelative to the solvent peak at 3.3 ppm) δ 8.60 (s, 1H) 8.37 (d, 2H)7.93 (d, 1H) 7.71 (t, 1H) 7.59 (d, 1H) 7.00 (d, 2H) 6.75 (t, 1H) 4.74(d, 1H) 4.65 (s, 2H) 4.60 (d, 1H) 4.06 (d, 2H) 3.85 (d, 1H) 3.65 (d, 2H)3.63 (d, 1H) 2.78 (d, 1H) 2.37 (d, 1H).

Intermediate 144:2-[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-1,1-dioxo-1λ⁶-[1,2,5]thiadiazepane-5-carboxylicacid tert-butyl ester: To a suspension of Intermediate 1 (10 g, 42 mmol)in methanol (150 mL) cooled to 0° C. (ice bath) add sodium borohydride(1.9 g, 1.2 equiv). Remove the ice bath and stir for 2-3 hr. Quench thereaction mixture with sodium bicarbonate (saturated solution, 50 mL) andconcentrate on the rotovap to remove most of the methanol. Dilute withethyl acetate (400 mL) and wash with brine. Dry the ethyl acetate layerwith (MgSO₄), filter and concentrate on the rotovap. Purify the crudematerial on silica gel (30-60% ethyl acetate/hexanes) to obtain thealcohol as a white solid. Yields are typically 60-80%.

To a suspension of the alcohol prepared from the reduction ofIntermediate 1 (10 g, 42 mmol) in CH₂Cl₂ (300 mL) add Hunig's base (11.2mL, 1.5 equiv) and methanesulfonic anhydride (8.8 g, 50 mmol, 1.2equiv). Stir the solution for 2-3 hr and poured over water (100 mL).Extract the water layer with CH₂Cl₂, dry (MgSO₄), filter andconcentrate. Purify the crude material on silica gel (30-60% ethylacetate/hexanes) to obtain the mesylate a white solid. Yields aretypically 50-70%.

To a solution of 1.2 g (3.4 mmol) of the mesylate and 1.0 g (4.0 mmol)of 1,1-dioxo-1λ⁶-[1,2,5]thiadiazepane-5-carboxylic acid tert-butyl ester(prepared according to literature procedure⁴) in 40 mL of THF add 0.23 g(10 mmol) of sodium hydride and stir at rt overnight. Quench with 50 mLof water and extract the reaction mixture 3× with ethyl acetate. Dry thecombined organic layers (Na₂SO₄), filter and concentrate on the rotavap.Purify the crude material on silica gel (70% ethyl acetate/hexanes) toobtain the intermediate as a white solid (62% yield). LC-MS showed theproduct had the expected M+H⁺ of 453.

Compound 270:4-(2-{4-[3-(1,1-Dioxo-1λ⁶-[1,2,5]thiadiazepan-2-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol:Intermediate 144 was coupled with tyramine following procedure F. Theresulting product was deprotected following procedure G2. LC-MS showedthe product had the expected M+H⁺ of 454. ¹H NMR (Varian 300 MHz, CD₃OD,shifts relative to the solvent peak at 3.3 ppm) δ 8.36 (s, 1H) 8.30 (d,1H) 8.20 (d, 1H) 7.73 (d, 1H) 7.64 (t 1H) 7.53 (d, 1H) 7.14 (d, 2H) 6.68(d, 2H) 4.70 (s, 2H) 3.80 (t, 2H) 3.67 (m, 4H) 3.56 (t, 2H) 3.36 (t, 2H)2.95 (t, 2H).

Intermediate 145: 3-(2-chloropyrimidin-4-yl)-4-methoxybenzaldehyde: 2,4dichloropyrimidine and 5-formyl-2-methoxyphenylboronic acid was coupledfollowing procedure A. The yield was 70%. LC-MS showed the productwas >95% pure and had the expected M+H⁺ of 249. ¹H NMR (Varian 300 MHz,MeOD-d₆, shifts relative to the solvent peak at 3.33 ppm) δ 9.9 (s, 1H)8.7 (d, 1H) 8.4 (s, 1H) 8.0 (d, 2H) 7.4 (d, 1H) 3.9 (s, 3H).

Intermediate 146: (3S)-tert-butyl4-(3-(2-chloropyrimidin-4-yl)-4-methoxybenzyl)-3-methylpiperazine-1-carboxylate:The product from the above reaction and (S)-tert-butyl3-methylpiperazine-1-carboxylate was coupled by procedure B. The yieldwas 84%. LC-MS showed the product had the expected M+H⁺ of 433.

Compound 271: 4-(2-(4-(2-methoxy-5(((S)-2-methylpiperazin-1-yl)methy1)phenyl)pyrimidin-2-ylamino)ethyl)phenol: Intermediate 146 from abovewas coupled with tyramine following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 434. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to thesolvent peak at 2.49 ppm) δ 8.4 (d, 1H) 7.8 (s, 1H) 7.3 (d, 1H) 7.1 (m,3H), 6.6 (m, 3H), 3.9 (s, 3H) 3.6 (m, 4H) 3.5 (d, 2H) 3.43-3.37 (m, 2H)3.2 (m, 2H) 2.8 (t, 2H), 1.5 (d, 3H).

Compound 272:2-chloro-4-(2-(4-(2-methoxy-5(((S)-2-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 146 from above was coupled with4-(2-aminoethyl)-2-chlorophenol following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 468. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to thesolvent peak at 2.49 ppm) δ 8.4 (d, 1H) 7.8 (d, 1H) 7.4-7.2 (m, 3H) 7.1(m, 2H), 6.1 (d, 1H), 3.9 (s, 3H) 3.7-3.6 (m, 4H) 3.5 (d, 2H) 3.4-3.3(m, 4H), 3.2 (m, 1H), 2.8 (t, 2H), 1.6 (d, 3H).

Intermediate 147: 5-(2-chloropyrimidin-4-yl)nicotinaldehdye: 2,4dichloropyrimidine and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehdye wascoupled following procedure A. The yield was 34%. LC-MS showed theproduct was >95% pure and had the expected M+H⁺ of 220.

Intermediate 148: (3S)-tert-butyl445-(2-chloropyrimidin-4-yl)pyridine-3-yl)methyl)-3-methylpiperazine-1-carboxylate:Intermediate 147 from the above reaction and (S)-tert-butyl3-methylpiperazine-1-carboxylate was coupled by procedure B. The yieldwas 60%. LC-MS showed the product had the expected M+H⁺ of 404.

Compound 273:2-chloro-4-(2-(4-(5-(((S)-2-methylpiperazin-1-yl)methyl)pyridine-3-yl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 148 from above was coupled with4-(2-aminoethyl)-2-chlorophenol following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 439. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to thesolvent peak at 2.49 ppm) δ 9.4 (s, 1H) 9.1 (m, 2H) 8.5 (d, 1H) 7.5 (s,1H), 7.2 (d, 1H) 7.0 (d, 1H) 6.8 (d, 1H), 3.7-3.5 (m, 5H) 3.4-3.2 (m,6H), 2.8 (t, 2H), 1.5 (d, 3H).

Compound 274:4-(2-(4-(5-(((S)-2-methylpiperazin-1-yl)methyl)pyridine-3-yl)pyrimidin-2-ylamino)ethylphenol:Intermediate 148 from above was coupled with tyramine followingprocedure F. The product was deprotected by procedure G2. LC-MS showedthe product had the expected M+H⁺ of 405. ¹H NMR (Varian 300 MHz,DMSO-d₆, shifts relative to the solvent peak at 2.49 ppm) δ 9.4 (s, 1H)9.0 (m, 2H) 8.5 (d, 1H) 7.5 (s, 1H), 7.0 (d, 2H), 6.6 (d, 2H), 3.7-3.5(m, 5H) 3.4-3.3 (m, 6H), 2.8 (t, 2H), 1.6 (d, 3H).

Compound 275:N-(3-fluorophenethyl)-4-(5-(((S)-2-methylpiperazin-1-yl)methyl)pyridine-3-yl)pyrimidin-2-amine:Intermediate 148 from above was coupled with2-(3-fluorophenyl)ethanamine following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 407. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to thesolvent peak at 2.49 ppm) δ 9.4 (s, 1H) 9.0 (m, 2H) 8.5 (d, 1H) 7.4 (s,1H), 7.2 (t, 1H), 7.1 (m, 2H), 6.9 (d, 1H), 3.71-3.65 (m, 4H) 3.57 (d,2H), 3.47-3.44 (m, 1H), 3.39-3.31 (m, 4H), 2.9 (t, 2H), 1.6 (d, 3H).

Intermediate 149: 3-(2-chloro-6-methylpyrimidin-4-yl)benzaldehdye:2,4-dichloro-6-methylpyrimidine and 3-formyl phenyl boronic acid wascoupled following procedure A. The yield was 69%. LC-MS showed theproduct was >95% pure and had the expected M+H⁺ of 233. ¹H NMR (Varian300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 10.1(s, 1H) 8.6 (s, 1H), 8.4 (d, 1H), 8.1 (d, 1H), 7.7 (t, 1H), 7.5 (s, 1H)2.6 (s, 3H).

Intermediate 150: (3S)-tert-butyl4-(3-(2-chloro-6-methylpyrimdin-4-yl)benzyl)-3-methylpiperazine-1-carboxylate:Intermediate 149 from the above reaction and (S)-tert-butyl3-methylpiperazine-1-carboxylate was coupled by procedure B. The yieldwas 77%. LC-MS showed the product had the expected M+H⁺ of 417

Compound 276:2-chloro-4-(2-(4-methyl-6-(3-(((S)-2-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 150 from above was coupled with4-(2-aminoethyl)-2-chlorophenol following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 452. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to thesolvent peak at 2.49 ppm) δ 8.6 (d, 1H) 8.3 (d, 1H) 7.9 (d, 1H) 7.7 (t,1H), 7.5 (s, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 4.12-3.9 (m,5H) 3.8-3.47 (m, 6H), 2.9 (t, 2H), 2.6 (s, 3H), 1.6 (d, 3H).

Intermediate 151: (S)-tert-butyl4-(3-bromophenylsulfonyl)-3-methylpiperazine-1-carboxylate:3-bromobenzene-1-sulfonyl chloride and (S)-tert-butyl3-methylpiperazine-1-carboxylate was coupled following as follows:Dissolve 1 g (5 mmol) of the amine in 10 mL of methylene chloride. Add2.0 eq. of diisopropyl ethylamine. Cool to 0° C. and add 1.5 equivalentsof bromobenzene sulfonyl chloride dropwise (ca. 1 min) and stir for 5min. Warm to rt and stir for an additional 16 h. Work up by adding asaturated solution of NaHCO₃ and extracting with EtOAc. Wash the organiclayer with HCl (1 N) followed by NaHCO₃ and brine. Remove the solvent toafford crude, yellow oil. Purification of the sulfonamide derivative byBiotage on silica gel (99% MeOH/DCM) affords the desired product as ayellow oil. The yield was 55%. LC-MS showed the product was >95% pureand had the expected M+H⁺ of 420. ¹H NMR (Varian 300 MHz, CDCl₃, shiftsrelative to the solvent peak at 7.24 ppm) δ 7.9 (d, 1H) 7.72-7.65 (m,2H) 7.4 (t, 1H), 3.7 (m, 2H) 3.6 (m, 1H), 3.13-3.0 (m, 2H) 2.92-2.77 (m,2H), 1.4 (s, 12H) 1.0 (d, 3H).

Intermediate 152: (S)-tert-butyl3-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl)piperazine-1-carboxylate: (S)-tert-butyl4-(3-bromophenylsulfonyl)-3-methylpiperazine-1-carboxylate wascross-coupled to4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneas follows: Charge a round bottom flask with 1.1 equivalents4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane,3 mol % PdCl₂(dppf), and 3 equivalents potassium acetate. Purge withargon and add DMSO (2-mL) followed by 1.0 equivalent bromobenzenesulfonamide. Heat the mixture to 80° C., overnight, under argon. Add H₂O(2 mL) and extract with ethyl acetate (20 mL). Wash organic layer withH₂O and brine. Remove the solvent and purify the product by ISCO onsilica gel (ethyl acetate as eluent). The yield was 93%. LC-MS showedthe product was >95% pure and had the expected M+H⁺ of 467.

Intermediate 153: (3S)-tert-butyl4-(3-(2-chloropyrimidin-4-yl)phenylsulfonyl)-3-methylpiperazine-1-carboxylate:2,4-dichloropyrimidine and (S)-tert-butyl3-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl)piperazine-1-carboxylatewas coupled following procedure A. The yield was 90%. LC-MS showed theproduct was >95% pure and had the expected M+H⁺ of 453.

Compound 277:N-(3,5-difluorophenethyl)-4-(3-((S)-2-methylpiperazin-1-ylsulfonyl)phenyl)pyrimidin-2-amine:Intermediate 153 from above was coupled with2-(3,5-difluorophenyl)ethanamine following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 474. ¹H NMR (Varian 300 MHz, MeOD-d₆, shifts relative to thesolvent peak at 3.33 ppm) δ 8.7 (d, 1H) 8.5 (d, 1H) 8.4 (d, 1H) 8.1 (d,1H), 7.8 (t, 1H), 7.6 (d, 1H), 6.9 (d, 2H), 6.7 (s, 1H), 3.52-3.34 (m,4H) 3.26-3.15 (m, 2H), 3.11-3.01 (m, 5H), 1.2 (d, 3H).

Compound 278:2-Chloro-4-(2-(4-(3-((S)-2-methylpiperazin-1-ylsulfonyl)phenyl)pyrimidin-2-ylamino)ethylphenol:Intermediate 153 from above was coupled with4-(2-aminoethyl)-2-chlorophenol following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 489. ¹H NMR (Varian 300 MHz, DMSO-d₆, shifts relative to thesolvent peak at 2.49 ppm) δ 8.6 (d, 1H) 8.4 (m, 2H) 8.0 (d, 1H), 7.8 (t,1H), 7.3 (s, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H) 3.5 (m, 3H), 3.3(m, 3H), 3.1 (m, 2H), 2.9 (m, 1H), 2.7 (t, 2H), 1.1 (d, 3H).

Compound 279:N-(3-fluorophenethyl)-4-(3-((S)-2-methylpiperazin-1-ylsulfonyl)phenyl)pyrimidin-2-amine:Intermediate 153 from, above was coupled with2-(3-fluorophenyl)ethanamine following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 456. ¹H NMR (Varian 300 MHz, MeOD-d₆, shifts relative to thesolvent peak at 3.31 ppm) δ 8.6 (d, 1H) 8.5 (d, 1H) 8.4 (d, 1H), 8.1 (d,1H), 7.8 (t, 1H), 7.6 (d, 1H), 7.2 (t, 1H), 7.1 (d, 1H), 7.0 (d, 1H),6.8 (d, 1H), 3.9 (m, 3H), 3.4 (m, 1H), 3.3 (m, 2H), 3.2 (m, 2H), 3.1 (m,1H), 3.0 (t, 2H), 1.2 (d, 3H).

Compound 280:4-(2-(4-(3-((S)-2-methylpiperazin-1-ylsulfonyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 153 from above was coupled with tyramine followingprocedure F. The product was deprotected by procedure G2. LC-MS showedthe product had the expected M+H⁺ of 454. ¹H NMR (Varian 300 MHz,MeOD-d₆, shifts relative to the solvent peak at 3.31 ppm) δ 8.6 (d, 1H)8.5 (d, 1H) 8.3 (d, 1H), 8.1 (d, 1H), 7.8 (t, 1H), 7.6 (d, 1H), 7.1 (d,2H), 6.6 (d, 2H), 3.9-3.8 (m, 3H), 3.4-3.3 (m, 2H), 3.2-3.1 (m, 3H),3.0-2.9 (m, 3H), 1.2 (d, 3H).

Intermediate 154: (3-bromo-4-methylphenyl)methanol: Ethyl3-bromo-4-methylbenzoate was reduced follows: 2 equivalents lithiumaluminium hydride (LAH) in THF was cooled to 0° C. Ethyl3-bromo-4-methylbenzoate in anhydrous THF (10 mL) was added slowly tothe cooled solution of LAH over 10 minutes, while stirring. The mixturewas stirred at room temperature for 1 hour. The reaction was cooled to0° C. and poured into ether (100 mL). The mixture was acidified byadding 1N HCl (aqueous) dropwise over 10 minutes. Separate fractions andwash aqueous phase with ether (50 mL). The fractions were combined anddried over magnesium sulfate. Solvent removal left a clear oil. Theyield was 90%. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to thesolvent peak at 7.24 ppm) δ 7.5 (s, 1H) 7.2 (d, 1H) 7.1 (d, 1H), 4.6 (s,2H) 2.3 (s, 3H).

Intermediate 155: 3-bromo-4-methylbenzaldehyde:(3-bromo-4-methylphenyl)methanol was oxidized as follows: To the primaryalcohol (15 mmol) in methylene chloride (30 mL) was added 10 equivalentsof activated manganese oxide (IV). The mixture was stirred at roomtemperature for 24 hours, the filtered through a bed of celite. Removalof the solvent left a yellow solid. Product was used crude in next stepwithout further purification. The yield was 89%. ¹H NMR (Varian 300 MHzCDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 9.8 (s, 1H)8.0 (s, 1H) 7.7 (d, 1H), 7.2 (d, 1H), 2.3 (s, 3H).

Intermediate 156:4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde:3-bromo-4-methylbenzaldehyde was cross-coupled to4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneas follows: Charge a round bottom flask with 1.1 equivalents4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane,3 mol % PdCl₂(dppf), and 3 equivalents potassium acetate. Purge withargon and add DMSO (2-mL) followed by 1.0 equivalent bromobenzenesulfonamide. Heat the mixture to 80° C., overnight, under argon. Add H₂O(2 mL) and extract with ethyl acetate (20 mL). Wash organic layer withH₂O and brine. Remove the solvent and purify the product by ISCO onsilica gel (ethyl acetate as eluent). The yield was 60%. LC-MS showedthe product was >95% pure and had the expected M+H⁺ of 246. ¹H NMR(Varian 300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm)δ 9.9 (s, 1H), 8.2 (s, 1H) 7.7 (d, 1H), 7.3 (d, 1H), 2.5 (s, 3H), 1.3(s, 12H).

Intermediate 157: 3-(2-chloropyrimidin-4-yl)-4-methylbenzaldehyde: 2,4dichloropyrimidine and4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde wascoupled following procedure A. The yield was 80%. LC-MS showed theproduct was >95% pure and had the expected M+H⁺ of 233. ¹H NMR (Varian300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 10.0(s, 1H) 8.7 (s, 1H) 7.9 (d, 2H) 7.5 (d, 2H), 2.5 (s, 3H).

Intermediate 158: (3S)-tert-butyl4-(3-(2-chloropyrimidin-4-yl)-4-methylbenzyl)-3-methylpiperazine-1-carboxylate:The product from the above reaction and (S)-tert-butyl3-methylpiperazine-1-carboxylate was coupled by procedure B. The yieldwas 60%. LC-MS showed the product had the expected M+H⁺ of 417.

Compound 281:4-(2-(4-(2-methyl-5-(((S)-2-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 158 from above was coupled with tyramine followingprocedure F. The product was deprotected by procedure G2. LC-MS showedthe product had the expected M+H⁺ of 418. ¹H NMR (Varian 300 MHz,MeOD-d₆, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H)8.0 (d, 1H) 7.7 (d, 1H) 7.5 (d, 1H), 7.3 (d, 1H), 7.0 (d, 2H) 6.7 (d,2H) 4.0 (t, 2H) 3.7 (m, 3H) 3.6-3.4 (m, 6H) 2.8 (t, 2H), 2.5 (s, 3H),1.7 (d, 3H).

Compound 283:N-(3,5-difluorophenethyl)-4-(2-methyl-5-(((S)-2-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-amine:Intermediate 158 from above was coupled with2-(3,5-difluorophenyl)ethanamine following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 438. ¹H NMR (Varian 300 MHz, MeOD-d₆, shifts relative to thesolvent peak at 3.31 ppm) δ 8.4 (d, 1H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (d,1H), 7.4 (d, 1H), 6.9 (d, 2H) 6.7 (t, 1H), 3.9-3.8 (m, 3H) 3.7-3.6 (m,6H) 3.5-3.4 (m, 2H) 3.0 (t, 2H), 2.5 (s, 3H), 1.7 (d, 3H).

Intermediate 159: 2-Chloro-4-(3-nitro-phenyl)-pyrimidine: 2,4dichloropyrimidine was coupled to 3-nitrophenyl boronic acid followingprocedure A. The workup and purification protocol was modified asfollows: The THF was removed from the reaction mixture by rotaryevaporation and the residue taken up in ethyl acetate. The solution waswashed with water followed by sat. NaCl and the organic layerconcentrated by rotary evaporation until the product started toprecipitate, at which point the flask was placed in an ice bath for twohours. The product was collected by filtration in a Buchner funnel. Theyield was 60%. Product was >95% pure by LC-MS and showed the expectedM+H⁺ of 236.

Intermediate 160: (3-bromo-2-methylphenyl)methanol: Ethyl3-bromo-2-methylbenzoic acid was reduced as follows: Add 5 equivalentsof borane tetrahydrofuran complex, via syringe, to 10 mmol ethyl3-bromo-2-methylbenzoic acid in tetrahydrofuran (5 mL). The mixture wasrefluxed for two hours, then cooled in an ice bath. Methanol (10 mL) wasadded dropwise, followed by 1 N HCl (50 mL). The solvent was removed andthe mixture partitioned between ethyl acetate and water. The yield was90%. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ7.5 (d, 1H) 7.2 (d, 1H) 7.1 (t, 1H), 4.6 (s, 2H) 2.3 (s,3H).

Intermediate 161: 3-bromo-2-methylbenzaldehyde:(3-bromo-2-methylphenyl)methanol was oxidized as follows: The alcohol(15 mmol) was dissolved in methylene chloride (30 mL). 10 equivalents ofactivated manganese oxide (IV) was added and the mixture stirred at roomtemperature for 24 hours. The mixture was filtered through a bed ofcelite and the solvent removed in-vacuo to leave yellow solid. Productwas used crude in next step without further purification. The yield was93%. ¹H NMR (Varian 300 MHz, CDCl₃, shifts relative to the solvent peakat 7.24 ppm) δ 9.8 (s, 1H) 8.1 (d, 1H) 7.7 (d, 1H), 7.2 (t, 1H), 2.4 (s,3H).

Intermediate 162:2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde:3-bromo-2-methylbenzaldehyde was cross-coupled to4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolaneas follows: A round bottom flask was charged with 1.1 equivalents4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane,3 mol % PdCl₂(dppf), and 3 equivalents potassium acetate. The flask waspurged with argon and DMSO (2-mL) added followed by 1.0 equivalentbromobenzene sulfonamide. The mixture was heated to 80° C., overnight,under argon. H₂O (2 mL) was added and the mixture extracted with ethylacetate (20 mL). The organic layer was washed with H₂O and brine.Removal of the solvent was followed and purification of the product byISCO on silica gel (ethyl acetate as eluent). The yield was 65%. LC-MSshowed the product was >95% pure and had the expected M+H⁺ of 246.

Intermediate 163: 3-(2-chloropyrimidin-4-yl)-2-methylbenzaldehyde: 2,4dichloropyrimidine and2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde wascoupled following procedure A. The yield was 50%. LC-MS showed theproduct was >95% pure and had the expected M+H⁺ of 233. ¹H NMR (Varian300 MHz, CDCl₃, shifts relative to the solvent peak at 7.24 ppm) δ 9.9(s, 1H) 8.6 (s, 1H) 7.5 (d, 2H) 7.4 (t, 1H), 7.2 (d, 1H), 2.5 (s, 3H).

Intermediate 164: (3S)-tert-butyl4-(3-(2-chloropyrimidin-4-yl)-2-methylbenzyl)-3-methylpiperazine-1-carboxylate:The product from the above reaction and (S)-tert-butyl3-methylpiperazine-1-carboxylate was coupled by procedure B. The yieldwas 60%. LC-MS showed the product had the expected M+H⁺ of 417.

Compound 284:4-(2-(4-(2-methyl-3-(((S)-2-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 164 from above was coupled with tyramine followingprocedure F. The product was deprotected by procedure G2. LC-MS showedthe product had the expected M+H⁺ of 418. ¹H NMR (Varian 300 MHz,MeOD-d₆, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H)8.0 (d, 1H) 7.7 (d, 1H) 7.5 (d, 1H), 7.3 (t, 1H), 7.0 (d, 2H) 6.6 (d,2H), 3.9 (t, 2H) 3.8-3.7 (m, 3H) 3.6-3.4 (m, 6H) 2.8 (t, 2H), 2.5 (s,3H), 1.7 (d, 3H).

Intermediate 165: 5-(2-chloropyrimidin-4-yl) 2-fluorobenzaldehyde: 2,4dichloropyrimidine and 4-fluoro-3-formylphenylboronic acid was coupledfollowing procedure A. The yield was 40%. LC-MS showed the productwas >95% pure and had the expected M+H⁺ of 237.

Intermediate 166: (3S)-tert-butyl4-(5-(2-chloropyrimidin-4-yl)-2-fluorobenzyl)-3-methylpiperazine-1-carboxylate:The product from the above reaction and (S)-tert-butyl3-methylpiperazine-1-carboxylate was coupled by procedure B. The yieldwas 50%. LC-MS showed the product had the expected M+H⁺ of 421.

Compound 285N-(3,5-difluorophenethyl)-4-(4-fluoro-3-(((S)-2-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-amine:Intermediate 166 from above was coupled with2-(3,5-difluorophenyl)ethanamine following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 442. ¹H NMR (Varian 300 MHz, MeOD-d₆, shifts relative to thesolvent peak at 3.31 ppm) δ 8.8 (d, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.7 (d,1H), 7.5 (t, 1H), 7.0 (d, 2H) 6.7 (d, 1H), 3.8-3.7 (m, 3H) 3.6-3.5 (m,8H), 3.0 (t, 2H), 1.7 (d, 3H).

Compound 286:4-(2-(4-(4-fluoro-3-(((S)-2-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 166 from above was coupled with tyramine followingprocedure F. The product was deprotected by procedure G2. LC-MS showedthe product had the expected M+H⁺ of 422. ¹H NMR (Varian 300 MHz,MeOD-d₆, shifts relative to the solvent peak at 3.31 ppm) δ 8.7 (d, 1H)8.4 (d, 1H) 8.3 (d, 1H) 7.6 (d, 1H), 7.5 (t, 1H), 7.1 (d, 2H) 6.6 (d,1H), 3.9-3.7 (m, 3H) 3.69-3.57 (m, 8H), 2.9 (t, 2H), 1.7 (d, 3H).

Compound 287:N-(3-fluorophenethyl)-4-(4-fluoro-3-(((S)-2-methylpiperazin-1-yl)methy1)phenyl)pyrimidin-2-amine: Intermediate 166 from above was coupled with2-(3-fluorophenyl)ethanamine following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 424. ¹H NMR (Varian 300 MHz, MeOD-d₆, shifts relative to thesolvent peak at 3.31 ppm) δ 8.8 (d, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.6 (d,1H), 7.5 (t, 1H), 7.2 (d, 1H) 7.1 (d, 2H), 6.8 (d, 1H), 3.8-3.7 (m, 3H)3.69-3.62 (m, 8H), 3.0 (t, 2H), 1.7 (d, 3H).

Intermediate 167: 5-(2-chloropyrimidin-4-yl-1H-indole: 2,4dichloropyrimidine and 1H-indol-5-ylboronic acid was coupled followingprocedure A. The yield was 78%. LC-MS showed the product was >95% pureand had the expected M+H⁺ of 230. ¹H NMR (Varian 300 MHz, DMSO-d₆,shifts relative to the solvent peak at 2.49 ppm) δ 8.6 (d, 1H) 8.4 (s,1H) 8.0 (d, 1H) 7.9 (d, 1H), 7.5 (d, 2H), 6.5 (d, 1H).

Compound 288:4-(2-(4-(1H-indol-5-yl)pyrimidin-2-ylamino)ethyl)-2-chlorophenol:Intermediate 167 from above was coupled with4-(2-aminoethyl)-2-chlorophenol following procedure F. LC-MS showed theproduct had the expected M+H⁺ of 365. ¹H NMR (Varian 300 MHz, MeOD-d₆,shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.1 (s,1H) 7.9 (d, 1H) 7.4 (d, 1H), 7.3 (d, 1H), 7.2 (s, 1H) 7.1 (d, 1H), 7.0(d, 1H), 6.8 (d, 1H) 6.5 (d, 1H), 3.6 (t, 2H), 2.8 (t, 2H).

Intermediate 168: 3-(2-Chloro-pyrimidin-4-yl)-benzaldehyde: 2,4dichloropyrimidine and 3-formyl phenyl boronic acid were coupledfollowing procedure A. The yield was 60%. LC-MS showed the productwas >95% pure and had the expected M+H⁺ of 219. ¹H NMR (Varian 300 MHz,CDCl₃, shifts relative to the solvent peak at 7.24 ppm) 10.1 (s, 1H) 8.7(d, 1H) 8.6 (m, 1H) 8.4 (m, 1H) 8.1 (m, 1H) 7.7 (m, 2H).

Intermediate 169: tert-butyl2-(2-(3-(2-chloropyrimidin-4-yl)benzylamino)ethyl)piperidine-1-carboxylate:The product from the above reaction and tert-butyl2-(2-aminoethyl)piperidine-1-carboxylate were coupled by procedure B.The yield was 40%. LC-MS showed the product had the expected M+H⁺ of431.

Intermediate 170: tert-butyl2-(2-((3-(2-chloropyrimidin-4-yl)benzyl)(ethyl)amino)ethylpiperidine-1-carboxylate:The product from the above reaction was coupled with acetaldehyde byprocedure C. The yield was 90%. LC-MS showed the product had theexpected M+H⁺ of 460.

Compound 289:2-chloro-4-(2-(4-(3-((ethyl(2-(piperidin-2-yl)ethyl)amino)methyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 170 from above was coupled with4-(2-aminoethyl)-2-chlorophenol following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 495. ¹H NMR (Varian 300 MHz, MeOD-d₆, shifts relative to thesolvent peak at 3.31 ppm) δ 8.4 (d, 1H) 8.2 (d, 1H) 8.1 (s, 1H), 7.5 (d,2H), 7.2 (t, 1H) 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H) 3.7 (d, 2H), 3.6(t, 2H), 2.98-2.92 (m, 1H), 2.90-2.68 (m, 8H), 1.98-1.87 (m, 1H),1.79-1.64 (m, 4H), 1.61-1.51 (m, 1H), 1.45-1.29 (m, 2H), 1.2 (t, 3H).

Compound 290:4-(3-((ethyl(2-(piperidin-2-yl)ethyl)amino)methyl)phenyl)-N-(2-(thiophen-2-yl)ethyl)pyrimidin-2-amine:Intermediate 170 from above was coupled with 2-(thiophen-2-yl)ethanaminefollowing procedure F. The product was deprotected by procedure G2.LC-MS showed the product had the expected M+H⁺ of 450 ¹H NMR (Varian 300MHz, MeOD-d₆, shifts relative to the solvent peak at 3.31 ppm) δ 8.4 (d,1H) 8.3 (d, 1H) 8.1 (s, 1H), 7.5 (d, 2H), 7.19 (t, 1H) 7.13 (d, 1H), 6.9(m, 2H), 3.9 (d, 2H) 3.75-3.61 (m, 3H), 3.1 t 2H), 2.9 (m, 1H),2.84-2.62 (m, 5H), 1.92-1.85 (m, 1H), 1.78-1.51 (m, 5H), 1.44-1.26 (m,2H), 1.1 (t, 3H).

Compound 291:N-(3-fluorophenethyl)-4-(3-((ethyl(2-(piperidin-2-yl)ethyl)amino)methyl)phenyl)pyrimidin-2-amine:Intermediate 170 from above was coupled with2-(3-fluorophenyl)ethanamine following procedure F. The product wasdeprotected by procedure G2. LC-MS showed the product had the expectedM+H⁺ of 462. ¹H NMR (Varian 300 MHz, MeOD-d₆, shifts relative to thesolvent peak at 3.31 ppm) δ 8.4 (d, 1H) 8.2 (d, 1H) 8.1 (s, 1H), 7.5 (d,2H), 7.32-7.24 (m, 1H) 7.13-7.01 (m, 3H), 6.9 (t, 1H), 3.9 (d, 2H) 3.70(t, 2H), 2.9 (t, 2H), 2.86-2.63 (m, 8H), 1.97-1.85 (m, 1H), 1.79-1.51(m, 4H), 1.41-1.28 (m, 2H), 1.2 (t, 3H).

Intermediate 171:N-(3-(2-chloropyrimidin-4-yl)benzyl)-2-(pyridine-2-yl)ethanamine:Intermediate 25 from above and 2-(pyridine-2-yl)ethanamine was coupledfollowing procedure A. The yield was 60%. LC-MS showed the productwas >95% pure and had the expected M+H⁺ of 325.

Compound 292:2-chloro-4-(2-(4-(3-((2-(pyridinyl-2-yl)ethylamino)methyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 171 from above was coupled with4-(2-aminoethyl)-2-chlorophenol following procedure F. LC-MS showed theproduct had the expected M+H⁺ of 460. ¹H NMR (Varian 300 MHz, MeOD-d₆,shifts relative to the solvent peak at 3.31 ppm) δ 8.8 (d, 1H) 8.5 (t,2H) 8.3 (d, 2H), 8.1 (d, 1H), 8.0 (t, 1H) 7.9 (d, 1H), 7.7 (t, 1H), 7.6(d, 1H) 7.2 (d, 1H), 7.0 (d, 1H), 6.7 (d, 1H), 4.4 (s, 2H), 3.6 (m, 4H),2.9 (t, 2H), 1.9 (t, 2H).

Intermediate 172:N-(3-(2-chloropyrimidin-4-yl)benzyl)-2-(pyridine-3-yl)ethanamine:Intermediate 25 from above and 2-(pyridine-3-yl)ethanamine was coupledfollowing procedure A. The yield was 55%. LC-MS showed the productwas >95% pure and had the expected M+H⁺ of 325.

Compound 293:2-chloro-4-(2-(4-(3-((2(pyridine-3-yl)ethylamino)methyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 172 from above was coupled with4-(2-aminoethyl)2-chlorophenol following procedure F. LC-MS showed theproduct had the expected M+H⁺ of 460 ¹H NMR (Varian 300 MHz, MeOD-d₆,shifts relative to the solvent peak at 3.31 ppm) δ 8.50-8.43 (m, 2H)8.29 (d, 1H) 8.21 (s, 1H), 8.1 (d, 1H), 7.7 (d, 1H) 7.63-7.55 (m, 2H),7.42-7.38 (m, 1H), 7.19 (d, 1H) 7.09 (d, 1H), 6.99 (d, 1H), 6.8 (d, 1H),4.2 (s, 2H), 3.6 (t, 2H), 3.3 (t, 2H), 3.0 (t, 2H), 2.8 (t, 2H).

Intermediate 173:N-(3-(2-chloropyrimidin-4-yl)benzyl)-2-(pyridine-4-yl)ethanamine:Intermediate 25 from above and 2-(pyridine-3-yl)ethanamine was coupledfollowing procedure A. The yield was 60%. LC-MS showed the productwas >95% pure and had the expected M+H⁺ of 325.

Compound 294:2-chloro-4-(2-(4-(3-((2-(pyridine-4-yl)ethylamino)methyl)phenyl)pyrimidin-2-ylamino)ethyl)phenol:Intermediate 173 from above was coupled with4-(2-aminoethyl)-2-chlorophenol following procedure F. LC-MS showed theproduct had the expected M+H⁺ of 460. ¹H NMR (Varian 300 MHz, MeOD-d₆,shifts relative to the solvent peak at 3.31 ppm) δ 8.4 (d, 2H) 8.4 (s,1H) 8.29 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H) 7.66-7.56 (m, 2H), 7.36 (d,1H), 7.20 (d, 1H) 7.10 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 4.3 (s, 2H),3.6 (t, 2H), 3.3 (t, 2H), 3.0 (t, 2H), 2.8 (t, 2H).

The following references are cited in the experimentals:

-   1. WO2004058736 page 73-   2. Synlett 2001, 11, 1811-1812-   3. EP0754686 page 9-   4. WO 2002030931 page 62-63

An in vitro assay for detecting and measuring inhibition activityagainst PKC-theta isoform by candidate pharmacological agents is usefulfor evaluating and selecting a compound that modulates PKC-thetaisoform. An IC₅₀ value can be calculated after running the assay.Following is an assay protocol for measuring PKC-theta isoform.

Testing Assay

Per well of a 384 well plate, compounds at various concentrations in 5μL of 20% DMSO were pre-incubated for about 30 minutes at about 25° C.with 15 μL of full length PKC θ (Panvera Corporation) at 27 pM in anassay buffer (25 mM Hepes, pH 7.5, 5 mM DTT, 10 mM MgCl₂, 10 mM2-glycerophosphate, 12.5 μg/mL 1,2-dioleoyl-rac-glycerol, 10 μg/mLL-α-phosphatidyl-L-serine, 0.1% Bovine Serum Albumin). 10 μL of peptidesubstrate (biotin-(CH₂)₆— RFARKGSLRQKNV —CONH₂) at 300 nM+3 μM ATP wereadded to each well and incubated for about 1 hour before quenching with10 μL of 250 mM EDTA. 40 μL of detection buffer (25 mM Hepes, pH 7.5,100 mM KF, 0.1% Bovine Serum Albumin, 0.01% Tween20) containing 2 nManti-phospho antibody 2B9 (MBL International) labeled with europiumcryptate (Cis-Bio International) and 0.0064 μg/mLstreptavidin-allophycocyanin (Prozyme) was added to each well andincubated for two hours. Signal was then read on a Discovery HTRF(Packard). The ratio of emission from the europium cryptate at 615 nMand the streptavidin-allophycocyanin at 665 nM has previously been shownto be linear with enzyme concentration and time and was used todetermine the inhibition activity of candidate pharmacological agents.

A compound can be run through this assay and its corresponding IC₅₀inhibition value can be calculated from the assay data. Compounds havingthe formula I can exhibit PKC-theta isoform inhibitor activities ofvarying degrees. The PKC-theta isoform inhibition average IC₅₀ valuesfor the compounds of formula I generally range from >0 nM to about 1000nM, preferably, from about 0.01 nM to about 500 nM, more preferably,from about 0.01 nM to about 100 nM, even more preferably, from >0 nM toabout 25 nM, and yet even more preferably, from >0 nM to about 10 nM. Inpreferred embodiments, the inventive compounds are both potent andselective (e.g., 50%, 2×, 5×, etc., more selective over other PKCisoforms) inhibitors of the PKC-theta isoform. In some embodiments, thefollowing compounds have IC₅₀ values less than 100 nM: 1, 2, 5, 6, 8,22, 24, 26, 29, 36, 38, 40, 45, 48, 49, 50, 53, 54, 55, 60, 62, 64, 65,67, 68, 70-75, 77, 80, 81, 84-95, 97-101, 104, 107, 115-118, 120, 121,125, 126, 130, 131, 132, 134, 136-138, 142, 143, 146-149, 151-161,163-196, 200, 218, 223-231, 233-235, 238-244, 249, 254, 258-259,261-263, 265, 266, 268-274, 278, 280-282, 284, 286, 289, 292, and295-372.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments, which utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments, which have been represented by way of example.

1. A compound of formula I-A-i:

or a pharmaceutically acceptable salt thereof, wherein: Cy^(t) is phenyloptionally substituted by one to three independent occurrences of R⁹;each occurrence of R⁹ is independently selected from —OR^(B),—N(R^(B))C(O)R^(A), —N(R^(B))₂, halo, C₁₋₄aliphatic optionallysubstituted by halo, NO₂, —OS(O)₂R^(C), —S(O)R^(C), —N(R^(B))SO₂R^(A),or —S(O)₂N(R^(B))₂; each occurrence of R^(A) is independently H,C₁₋₃alkyl or C₃₋₅cycloalkyl; each occurrence of R^(B) is independently Hor C₁₄ aliphatic; or two R^(B) on the same nitrogen atom taken togetherwith the nitrogen atom form a 5-8 membered aromatic or non-aromatic ringhaving in addition to the nitrogen atom 0-2 ring heteroatoms selectedfrom N, O or S; and each occurrence of R^(C) is independently C₁₋₄aliphatic; ring A is optionally substituted with 1 or 2 independentoccurrences of R⁵, wherein R⁵ on ring A, when present, is selected fromF, Cl, Br, or methyl; W is L₁—R⁷, L₁ is an optionally substituted C₁₋₆alkylene chain; R⁷ is H, halo, —OH, —N(R^(F))₂, —CN, —OR^(G),—C(O)R^(G), —CO₂H, —CO₂R^(G), —SR^(G), —S(O)R^(G), —S(O)₂R^(G),—N(R^(E))C(O)R^(G), —N(R^(E))CO₂R^(G), —N(R^(E))SO₂R^(G),—C(O)N(R^(F))₂, —SO₂N(R^(F))₂,—N(R^(E))C(O)N(R^(F))₂, —OC(O)R^(F) or anoptionally substituted group selected from C₁₋₁₀ aliphatic, C₆₋₁₀aryl,3-14 membered heterocyclyl or 5-14 membered heteroaryl, wherein eachoccurrence of R^(F) is independently H, C₁₋₆ aliphatic, C₆₋₁₀aryl, 3-14membered heterocyclyl, 5-14 membered heteroaryl, —C(═O)R^(B),—C(O)OR^(B) or —SO₂R^(B); or two R^(F) on the same nitrogen atom takentogether with the nitrogen atom form an optionally substituted 5-8membered aromatic or non-aromatic ring having in addition to thenitrogen atom 0-2 ring heteroatoms selected from N, O or S; and eachoccurrence of R^(G) is C₁₋₆ aliphatic, C₆₋₁₀aryl, 3-14 memberedheterocyclyl, or 5-14 membered heteroaryl.
 2. The compound of claim 1,wherein Cy² is optionally substituted with one, two or three occurrencesof R⁹, wherein each occurrence of R⁹ is independently selected from haloor —OH.
 3. The compound of claim 1, wherein R⁷ is selected from —NH₂,—NH(C₁₋₅alkyl), —N(C₁₋₅alkyl)₂, —NHCO₂(C₁₋₆alkyl), —NHCO(C₁₋₆alkyl),—NHCO(optionally substituted phenyl), —NHSO₂(C₁₋₆alkyl), or anoptionally substituted group selected from C₁₋₆alkyl, phenyl, pyridyl,piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl.
 4. The compoundof claim 1, wherein the optionally substituted group in R⁷ is optionallysubstituted at one or more carbon atoms with one, two or threeindependent occurrences of R¹¹, and at one or more substitutablenitrogen atoms with R¹², wherein each occurrence of R¹¹ is independentlyselected from optionally substituted C₁₋₆aliphatic, optionallysubstituted 6-10-membered aryl, optionally substituted 5-10-memberedheteroaryl, —N(R^(B))₂, ═O, halo, NO₂, —CN, —OR^(B), —C(O)R^(A),—CO₂R^(A), —SR^(C) —S(O)R^(C), —S(O)₂R^(C), —OS(O)₂R^(C),—N(R^(B))C(O)R^(A), —N(R^(B))SO₂R^(A), —N(R^(B))SO₂R^(A),—C(O)N(R^(B))₂, —SO₂N(R^(B))₂, —N(R^(B))C(O)N(R^(B))₂, or —OC(O)R^(A),and each occurrence of R¹² is independently selected from H, optionallysubstituted C₁₋₆ aliphatic, optionally substituted 6-10-membered aryl,optionally substituted 5-10-membered heteroaryl, —C(═O)R^(B),—C(O)OR^(B) or —SO₂R^(B).
 5. The compound of claim 1 wherein R⁷ ispiperidinyl.
 6. The compound of claim 1, wherein L₁ is an optionallysubstituted C₁—C₄ alkylene.
 7. The compound of claim 1, wherein L₁ is—(CH₂)_(n), where n is 1-2, and wherein one hydrogen atom on anymethylene unit is optionally substituted with C₁₋₃alkyl, —OH,—O(C₁₋₃alkyl), —COOH, or —COO(C₁₋₃alkyl).
 8. The compound of claim 1,wherein ring A is optionally substituted with 1 occurrence of R⁵,wherein R⁵ on ring A, when present is F.
 9. The compound of claim 1,wherein the compound is:


10. A pharmaceutical composition comprising the compound orpharmaceutically acceptable salt according to claim 1 and apharmaceutically acceptable excipient or carrier.
 11. A pharmaceuticalcomposition comprising: a) the compound or pharmaceutically acceptablesalt according to claim 1, b) methotrexate or a pharmaceuticallyacceptable salt thereof, and c) a pharmaceutically acceptable excipientor carrier.